BirthDefects2008AnnualReport.txt

BirthDefects2008AnnualReport.txt





<p>Birth Defects Research: <br />Diagnosis; Treatment; Prevention <br /> <br />Those of us lucky enough to call ourselves developmental biologists <br />have, for the past several decades, had front row seats at one of <br />the most fascinating plays ever seen…a play entitled ”Embryonic <br />Development.” Intense scientific inquiry into molecular and cellular <br />processes during development has revealed secrets long hidden by <br />the developing embryo, transforming the field of developmental biology <br />from a descriptive into a predictive science. Embryogenesis is no longer <br />an arcane process. We are witnessing a play wherein genes, molecules <br />and proteins are the actors, interacting—in ways that we increasingly <br />understand—to create, by the final scene, a healthy baby. <br />Imagine each member of the audience of this play being shown the <br />sequence of their own genome. They would see a line of A’s, T’s, <br />G’s, and C’s three billion letters in length. The letters, represent the <br />structural units of DNA used to spell out the genetic instructions used <br />in development, each unique sequence defining who we are. A printed <br />version of this personal “Book of Life,” using the font size you see here, <br />would be over 30,000 pages long. Astonishingly, this is packaged into <br />a single cell, and using only 25,000 or so genes, this blueprint is used <br />to construct a human being. Yet despite the immense complexity <br />involved, most babies that are born are normal and healthy! One <br />cannot help but be amazed at Nature’s handiwork! <br />The more that is revealed about our <br />individual Book of Life, the more amazing <br />the story becomes. Since the unveiling <br />of the human genome in 2001, we have <br />moved from asking what in our DNA <br />makes us human to striving to know what <br />in one’s DNA makes individuals unique. <br />Indeed, recognition of the extent of <br />human genetic variation was considered <br />the 2007 “Breakthrough of the Year” <br />by Science magazine. There are over <br />15 million locations, known as “singlenucleotide <br />polymorphisms” (SNPs), in <br />our genomes where a single base can <br />differ from one person or population to <br />the next. A catalog of common genetic <br />variants that occur in human beings, <br />called the HapMap, describes these <br />variants and the location where they <br />occur in our DNA. This information is <br />being used by researchers to link genetic <br />variants to the risk for specific diseases <br />and should prove invaluable for defining risk factors for certain birth <br />defects. <br />Another form of genetic variation occurs when differences in the <br />number of copies of a particular region in the genome appear. Such <br />changes can result in an altered number of copies of a gene or piece <br />of regulatory DNA. Such “copy number variants,” as they are called, <br />have been associated with susceptibility or resistance to disease. Copy <br />number variants also appear to pose a risk to the developing fetus <br />since such variants have been associated with autism1,2, and idiopathic <br />learning disability3. <br />Despite these astounding advances in our knowledge, birth defects <br />continue to affect about one in every 33 babies born in the United <br />States each year, and are the leading cause of infant mortality. Each <br />year, over 3 million children die before the age of five as a result of <br />complications due to congenital anomalies4. Nearly twenty five percent <br />of all infant deaths in Kentucky are caused by congenital anomalies… <br />one of the highest rates in the nation. Indeed, more babies die because <br />of complications due to birth defects than from all other causes. <br />Despite ongoing research, the causes of nearly 70% of birth <br />defects remain unknown! Nevertheless, significant advances have <br />been achieved in our understanding of the causes and risk factors <br />associated with congenital anomalies. For example, we now know <br />that: obesity confers a higher risk of serious birth defects of the brain <br />and spine; dietary supplementation with folic acid lowers the risk of <br />having a baby with a neural tube defect; exposure to cigarette smoke <br />increases the risk of giving birth to a low birth weight baby or one with <br />a cleft palate; Accutane™, a drug used to treat severe acne, during <br />pregnancy causes severe birth defects; and consumption of alcohol <br />(wine, beer, or liquor) is the leading known preventable cause of mental <br />and physical birth defects. <br />“In a scientific experiment, there are two possible outcomes: If the result <br />confirms the hypothesis, then you’ve made a measurement. If the result is <br />contrary to the hypothesis, then you’ve made a discovery” <br />—Enrico Fermi (1901-1953) <br />2 <br />Message from the Director <br />1Science 316:445 (2007) <br />2Psychiatr Genet. 18:101-109 (2008) <br />3The Lancet 354: 1676 (1999) <br />4 March of Dimes, 2006 <br />The critical challenge for the Birth Defects Center at the University of <br />Louisville’s to improve the diagnosis and treatment of birth defects as <br />well as effect their prevention. To address this mission, investigators in <br />the Birth Defects Center are engaged in the conduct of fundamental <br />research on molecular and molecular genetic aspects of embryonic <br />development and congenital malformations. In the pages that follow, <br />it can be seen that the Birth Defects Center seeks to 1) examine how <br />genes and the environment work together to cause birth defects, 2) <br />enable prenatal molecular diagnosis of maternal genetic susceptibility <br />to potential fetal hazards such as exposure to tobacco, alcohol and <br />certain medications, and 3) define the etiology of developmental <br />abnormalities such as autism, neural tube defects, orofacial clefting, <br />holoprosencephaly, diabetic embryopathy, learning and cognitive <br />disorders, and idiopathic infertility as well as others. <br />While many examples of individual research support can be <br />acknowledged (see individual faculty profiles that follow), two <br />organizations require singular recognition: <br />1) Each year Kosair Charities (www.kosair.org) <br />donates millions of dollars to help support health <br />care organizations in Kentucky and southern <br />Indiana that specialize in treating children. During <br />the past several years, the University of Louisville <br />Birth Defects Center received significant support <br />from Kosair Charities. On belhalf of the University and the Center, I wish <br />to acknowledge this support which has made an important and positive <br />impact on our ability to address the missions of the Center. <br />2) For the past 5 years the National Center for Research Resources <br />(http://www.ncrr.nih.gov) at the NIH has supported a Center of <br />Biomedical Research Excellence (COBRE) whose purpose <br />was to foster interdisciplinary, health-related research aimed <br />at illuminating the molecular etiologies of developmental <br />defects and disabilities, and to enhance the competitiveness <br />of junior investigators for independent funding. Because <br />of success in achieving these goals, the COBRE was refunded by the <br />NCRR in 2008 for an additional 5 years in the amount of $8.8 million. <br />It is our hope that research activities conducted by members of the <br />Birth Defects Center will result in a tangible improvement in our ability to <br />diagnosis birth defects as well as lead to intervention strategies resulting <br />in the reduction of the frequency of birth defects. For those of you that <br />read on—once again, enjoy the journey! <br />Robert M. Greene, Ph.D. <br />3 <br />“The great tragedy of science — the slaying of a <br />beautiful hypothesis by an ugly fact” <br />—TH Huxley (1825-1895) <br />Adamkin DH. Controversies in Neonatal <br />Nutrition: Docosahexanoic Acid (DHA) and <br />Nucleotides. J Perinatol 27:S79-82 (2007). <br />Bhatia J, Young TE, Adamkin DH. Discussion 4: <br />Nutritional Update. J Perinatol 27:S83 (2007). <br />Adamkin DH. Early Aggressive Nutrition: Parenteral Amino Acids and <br />Minimal Enteral Nutrition for Extremely Low Birthweight &lt;1000g Infants. <br />Edizioni Minerva Medica S.P.A. 59:369-377 (2007). <br />Batton DG, Adamkin DH, Bell EF, Denson SE, Engle WA, Martin GI, <br />Stark AR. Barrington KJ, Raju T N.K., Riley LR, Tomashek KM, Wallman <br />C, Couto J. Co-Bedding Twins and Higher-Order Multiples in a Hospital <br />Setting. Pediatrics 120:1359-1366 (2007). <br />Adamkin DH. Use of Intravenous Lipids in <br />Very Low Birthweight Infants. NeoReviews <br />8(12): e543-e546 (2007). <br />Engle WA, Tomashek KM, Wallman C, <br />Adamkin DH, Barrington KJ, Batton DG, Bell <br />EF, Couto J, Denson SE, Martin GI, Stark AR, <br />Raju T N.K., Riley LR. Late- Preterm Infants: A <br />Population at Risk. Pediatrics 120:1390-1401 <br />(2007). <br />Adamkin DH. Nutritional Rehabilitation for Brain Injured Infants: <br />Catch-Up Growth is Good! Invited commentary, Pediatrics, 121(1):181- <br />182 (2008). <br />Engle WA, Blackmon LR, Stark AR, Adamkin DH (COFN), Batton, DG, <br />Bell EF, Denson SE, Martin GI, Bhutani VK. Surfactant-Replacement <br />Therapy in the Neonate. Pediatrics 121(2):419-432 (2008). <br />Abbasi SA, Stewart DL, Radmacher PG, Adamkin DH. Natural Course <br />of Cholestasis in Neonates on Extracorporeal Membrane Oxygenation <br />(ECMO): 10 Year Experience at a Single Institution. ASAIO J 54 (4): <br />436-438, (2008). <br />Committee on the Fetus and Newborn, American Academy of <br />Pediatrics, Post-discharge follow up of infants with congenital <br />diaphragmatic hernia. Pediatrics 121(3):627-632 (2008). <br />Research Activities: <br />David Adamkin, MD, serves as Director of the Division of Neonatal <br />Medicine and the Neonatal Nutrition Research Lab with 15 faculty and 7 <br />neonatal fellows. Additionally, he is a member of the Committee on the <br />Fetus and Newborn of the American Academy of Pediatrics. In 2007 <br />and 2008, he gave 88 scientific presentations in the USA, Canada and <br />Poland as well as serving as a visiting professor in the United States <br />and Poland. Recent research has focused on growth strategies in <br />preterm infants both during hospitalization and after discharge. He has <br />produced 11 peer reviewed publications, 2 book chapters, 6 books/ <br />educational videos in the years 2007-08. <br />Grants Funded: <br />Role: Principal Investigator <br />Title: Fetal and Infant Mortality Review (FIMR) <br />Funding Agency: Adult and Child Health Improvement, Cabinet <br />for Health Services: Department of Public Health and Family Services <br />Direct Costs Funded: $20,000 <br />Role: Co-Principal Investigator <br />Title: Lactoferrin enhances growth and reduces nosocomial infection <br />in preterm infants <br />Funding Agency: Agennix <br />Direct Costs Funded: $86,363 <br />Peer-reviewed Publications: <br />Batton DG, Adamkin DH, Bell EF, Denson SE, Engle WA, Martin GI, <br />Stark AR. Barrington KJ, Raju T N.K., Riley LR, Tomashek KM, Wallman <br />C, Couto J. Non-initiation or Withdrawal of Intensive Care for High-Risk <br />Newborns. Pediatrics 119:401-403 (2007). <br />4 <br />David Adamkin, M.D. <br />Professor <br />Department of Pediatrics <br />Director <br />Division of Neonatal Medicine <br />Director <br />Neonatal Fellowship Program <br />Director <br />Nursery at Norton’s Hospital <br />Director <br />Neonatal Nutrition Research <br />Program <br />Associate Professor of Obstetrics <br />School of Medicine <br />Research Activities <br />Dr. Brock’s research interests include statistical genetics and the <br />analysis of microarray data. He is also interested in developing <br />methods for handling proteomic data. <br />Grants Funded <br />Role: Statistical Core <br />Title: Molecular Determinants of Developmental Defects <br />Funding Agency: NIH/NCRR <br />Direct Costs Funded: $297,367 (core only) <br />Role: Statistical Consultant <br />Title: Center for Environmental Genomics and Integrative Biology <br />Bioinformatics, Biostatistics and Computational Biology Core <br />Funding Agency: NIH/NIEHS <br />Direct Costs Funded: $600,000 (core only) <br />Role: Co-Investigator <br />Title: Transcriptional Coactivators and Pregnancy Outcomes <br />Funding Agency: NIH <br />Direct Costs Funded: $255,546 <br />Role: Co-Investigator <br />Title: Nutritional Epigenetics and Orofacial <br />Development <br />Funding Agency: NIH <br />Direct Costs Funded: $250,000 <br />Role: Co-Investigator, <br />Biostatistician <br />Title: A Pharmacogenetic <br />Approach to Prostate Cancer <br />Susceptibility <br />Funding Agency: National <br />Cancer Institute, NIH <br />Direct Costs Funded: $50,000 <br />Peer-reviewed Publications <br />Brock, G., Weeks, D.E., Sobel, E. and Feingold, E. (2007) “A novel <br />method for estimating significance levels in NPL scores for large <br />pedigrees” Genet Epidemiol., 31(5):417-430. <br />Brock, G., Shaffer, J.R., Blakesley-Ball, R.E., Lotz, M.J., and Tseng, <br />G.C. (2008) “Which missing value imputation method to use in <br />Guy Brock <br />Assistant Professor <br />Department of Bioinformatics <br />School of Public Health &amp; <br />Information Sciences <br />expression profiles: a comparative study and two selection schemes” <br />BMC Bioinformatics 9(1):12 <br />Bordon, J., Peyrani, P., Brock, G., Blassi, F., Rello, J., File, T., Ramirez, <br />J.A., and the CAPO Study Group. “The care of hospitalized patients <br />with community-acquired pneumonia should not be altered by the <br />presence of pneumococcal bacteremia: Results from the communityacquired <br />pneumonia organization (CAPO) international cohort study.” <br />CHEST, 2008. 133(3):618-24 <br />Pihur, V., Brock, G., Datta, S. and Datta, S. “Cluster validation for <br />microarray data: An appraisal”. In Indian Statistical Institute Platinum <br />Jubilee Series (A. SenGupta, Ed), World Scientific Press, to appear <br />(2008). <br />Bhattacharjee, S., Kuo, C-L., Mukhopadhyay, N., Brock, G., Weeks, <br />D.E., and Feingold, F. (2008) “Robust score statistics for QTL linkage <br />analysis” The American Journal of Human Genetics 82(3):567-82. <br />Brock, G., Pihur, V., Datta, S., and Datta, S. (2008) “clValid, an R <br />package for cluster validation” Journal of Statistical Software Vol. 25, <br />Issue 4, Mar 2008. <br />Brock, G., Beavis, W., and Salter, L. (2008) “Fuzzy and related <br />methods as screening tools fordetecting gene regulatory Networks,” <br />Information Fusion (in press). <br />5 <br />Research Activities <br />The neural development requires both genetic (intrinsic) and <br />environmental (extrinsic) factors at different embryonic and postnatal <br />stages. Either lack is destined for CNS dysplasia. Our general <br />research goal is to understand molecular pathways and genetic <br />programs that control the CNS development. Currently it focuses <br />on transcriptional regulation on the generation, specification and <br />differentiation of both neuronal and glial cells, which is a pivotal <br />intrinsic mechanism to control neural cell fate. In addition, we are <br />also interested in how environmental factors affect this process. The <br />study aims: (1) to identify and characterize candidate genes that <br />are specifically expressed in neurons or glias; (2) to investigate the <br />‘molecular switches’ in CNS that are involved in hypoxia, aging, or <br />developmental and neurological disorders such as attention-deficit <br />hyperactivity disorder (ADHD), autism, multiple sclerosis (MS), <br />amyotrophic lateral sclerosis (ALS) etc; (3) to develop molecular <br />and/or cellular strategies for preventive or therapeutic purpose. <br />The experimental approaches cover molecular cloning, RNA in situ <br />hybridization, immunohistochemistry, Western blot, gene targeting, <br />in ovo electroporation, and in vitro explant or stem cell culture. The <br />electrophysiological and neurobehavioral assessments are also <br />performed for functional analyses. Ongoing projects include: <br />• PAF signaling in normal CNS development. <br />• Oligodendroglial injury and sleep apnea-associated intermittent <br />hypoxia. <br />Grants Funded <br />Role: Principal Investigator <br />Title: Oligodendrocyte Generation in Prenatal Exposure to <br />Intermittent Hypoxia <br />Funding Agency: University of Louisville <br />Direct Costs Funded: $4,942 <br />Jun Cai, M.D., Ph.D. <br />Assistant Professor <br />Department of Pediatrics <br />School of Medicine <br />Role: COBRE Supported Junior Investigator <br />Title: Intermittent Hypoxia-mediated Oligodendrocytes Defects in a <br />Murine Model of Gestational Sleep Apnea <br />Funding Agency: NIH/NCRR, COBRE <br />Direct Costs Funded: $50,000 <br />Role: Principal Investigator <br />Title: Phenotype on Myelination and Myelin Architecture in Intermittent <br />Hypoxia Mouse Model <br />Funding Agency: University of Louisville School of Medicine <br />Direct Costs Funded: $14,964.15 <br />Peer-reviewed Publications <br />Liu Z, Hu X, Cai J, Liu B, Peng X, Wegner M, Qiu, M. Induction <br />of oligodendrocyte differentiation by Olig2 and Sox10: evidence <br />for reciprocal interactions and dosage-dependent mechanisms. <br />Developmental Biology 302: 683-693 (2007) <br />Zhang YP, Shields LB, Pei J, Zhang Y, Xu XM, Hoskins R, Cai J, <br />Qiu MS, Magnuson DS, Burke DA, Shields CB. Use of magnetic <br />stimulation to elicit motor evoked potentials, somatosensory evoked <br />potentials, and H-reflexes in non-sedated rodents. Journal of <br />Neuroscience Methods 165(1): 9-17 (2007). <br />6 <br />7 <br />Hoffman W, Casanova MF, Cudrici CD, Zakranskaia E, Venugopalan <br />R, Nag S, Oglesbee MJ, Rus H,. Neuroinflammatory response of the <br />choroids plexus epithelium in fatal diabetic ketoacidosis. Experimental <br />and Molecular Pathology 83(1):65-72, 2007. <br />El-Baz A, Casanova MF, Gimel’farb G, Mott M, Switala A. A New <br />Image Analysis Approach for Automatic Classification of Autistic Brains. <br />Proc.of IEEE International Symposium on Biomedical Imaging: From <br />Nano to Macro (ISBI’07), Arlington, Virginia, USA, April 12–15, 2007, <br />pp. 352-355. <br />Fahami R, Casanova MF, Farag A: Robust neuroimaging-based <br />classification techniques of autistic vs. typically developing brain, In: <br />Biomedical imaging: From nano to macro. Piscataway, NJ: IEEE; 352- <br />355, 2007. <br />El-Baz A, Casanova MF, Gimel’farb G, Mott M, Switala A. Autism <br />Diagnostics by 3D Texture Analysis of Cerebral White Matter <br />Gyrifications. Proc. of International Conference on Medical Image <br />Computing and Computer-Assisted Intervention (MICCAI’07), 10(Pt. 2): <br />882-890, 2007. <br />Casanova MF, Switala AE, Trippe J, Fitzgerald M. Comparative <br />minicolumnar morphometry of three distinguished scientists. Autism <br />11(6):557-569, 2007. <br />Casanova MF. Schizophrenia as a deficit in the modulation of cortical <br />minicolumns by monoaminergic systems. International Review of <br />Psychiatry 19(4): 361-372, 2007. <br />Fahmi R, El-Baz A, Hassan H, Farag A, Casanova MF. Classification <br />Techniques for Autistic Vs. Typically Developing Brain Using MRI Data, <br />Proc. of IEEE International Symposium on Biomedical Imaging: From <br />Nano to Macro (ISBI’07), Arlington, Virginia, USA, April 12–15, 2007, <br />pp. 1348-1351. <br />Abd EL Munim H, Farag AA, Casanova MF, Frequency-Domain <br />Analysis of the Human Brain for Studies of Autism, Proceedings, 7th <br />IEEE International Symposium on Signal Processing and Information <br />Technology, ISSPIT 2007, Cairo, Egypt, December 15-18, 2007, pp. <br />1198-1203. <br />Casanova MF, Kreczmanski P, Trippe J, Switala A, Heinsen H, <br />Steinbusch HWM. Schmitz S. Neuronal distribution in the neocortex of <br />schizophrenic patients. Psy Res 158(3):266-277, 2008. <br />Research Activities <br />The focus of the laboratory is the study of cortical circuitry abnormalities <br />in psychiatric conditions. Previous work established: 1) the validity <br />of the cell minicolumn as a template for cortical organization and, 2) <br />how interhemispheric differences in the morphometry of minicolumns <br />provided for the speciation of hominds. More recent studies have <br />looked for the presence of abnormalities of minicolumnar organization <br />and lateralization in the brains of patients who exhibit language <br />disturbances including, autism, Asperger’s syndrome, and dyslexia. <br />Grants Funded <br />Role: Principal Investigator <br />Title: Modular Abnormalities of Brain Organization in Autism <br />Funding Agency: National Institutes of Health <br />Direct Costs Funded: $540,000 <br />Role: Co-Investigator <br />Title: Mood Stabilizing Medications and the Inositol Signaling System <br />Funding Agency: Department of Veterans Affairs—VA Merit Review <br />Direct Costs Funded: $1,044,200 <br />Peer-reviewed Publications <br />Casanova MF, Switala A, Trippe J. A comparison study on the vertical <br />bias in neocortex and hippocampus. Developmental Neuroscience, <br />29(1-2):193-200, 2007. <br />Casanova MF, Trippe J, Switala AE: A temporal continuity to the <br />vertical organization of the human neocortex: a study spanning prenatal <br />development and aging. Cerebral Cortex, 17(1):130-137, 2007. <br />Gottfried &amp; Gisela Kolb Endowed Chair <br />in Psychiatry <br />Associate Chair of Research <br />Department of Psychiatry <br />School of Medicine <br />Manuel Casanova, M.D. <br />Casanova MF. The minicolumnopathy of autism: a link between <br />migraine and gastrointestinal symptoms. Medical Hypothesis, 70:73- <br />80, 2008. <br />Casanova MF, Tillquist C. Encephalization, emergent properties, and <br />psychiatry: a minicolumnar perspective. The Neuroscientist, 14:101- <br />118, 2008. <br />Seelan RS, Khalyfa A, Lakshmanan J, Casanova MF, Parthasarathy <br />RN. Deciphering the lithium transcriptome: microarray profiling <br />of lithium modulated gene expression in human neuronal cells. <br />Neuroscience, 151(4): 1184-1197, 2008. <br />Casanova MF, Konkachbaev AI, Switala AE, Elmaghraby AD. <br />Recursive trace line method for detecting myelinated bundles: a <br />comparison study with pyramidal cell arrays. Journal of Neuroscience <br />Methods, 168(2):367-372, 2008. <br />Fajardo C, Escobar MI, Buritca E, Artega G, Umbarilla H, Casanova <br />MF, Pimienta H. Von Economo neurons are present in the dorsolateral <br />(dysgranular) prefrontal cortex of humans. Neuroscience Letters <br />435(3):215-218, 2008. <br />El-Zehiry N, Casanova MF, Elmaghraby A. Variability of the relative <br />corpus callosum cross sectional area between dyslexic and normally <br />developed brains. International Symposium of Biomedical Engineering <br />(ISBI), in press. <br />El-Baz A, Casanova MF, Gime’farb G, Mott M, Switala, VanBogaert <br />E, McCracken R. Dyslexia diagnostic by 3D Texture analysis of cerebral <br />white matter gyrifications. IEEE International Conference on Image <br />Processing (San Diego, California), in press. <br />El-Baz A, Casanova MF, Gime’farb G, Mott M, Switala. An MRI-based <br />diagnostic framework for early diagnosis of dyslexia. International <br />Journal of Computer Assisted Radiology and Surgery, in press. <br />automatic orientation.png: A 35 µm thick section through human cortex <br />(Brodmann area 22) is shown, spanning a region 4.5 mm by 2.7 mm in <br />size. Arrows represent the local radial direction r' computed automatically <br />using the Fourier transform to detect anisotropy. The routine fails in lamina I, <br />where there is no columnar structure present in a Nissl stain, but otherwise <br />performs adequately. <br />El-Zehiry N, Casanova MF, Elmaghraby AS. Analyzing the <br />Development and the Functionality of Dyslexic and Autistic Brains <br />by Investigating the Relationship between the Microstructures and <br />Macrostructures. MICCAI 2008 Workshop on Imaging the Early <br />Developing Brain: Challenges and Potential Impact, in press. <br />Casanova MF, El-Baz A, Mott M, Mannheim G, Hassan H, Fahmi <br />R, Rumsey JM, Switala AE, Farag A. Reduced gyral window and <br />corpus callosm size in autism: possible macroscopic correlates of a <br />minicolumnopathy. Journal of Autism and Developmental Disorders, in <br />press. <br />Casanova MF, Trippe J, Tillquist C, Switala A. Morphometric variability <br />of minicolumns in the striate cortex of Homo sapiens Macaca mulatta, <br />and Pan troglodytes. Journal of Anatomy, in press. <br />Sokhadze E, El-Baz A, Singh S, Mathai G, Sears L, Casanova MF. <br />Evoked and induced gamma frequency oscillations, interhemispheral <br />coherence and event-related potential abnomarlities during processing <br />of illusory figures in autism spectrum disorders. JADD in press. <br />Chance SA, Casanova MF, Switala AE, Crow TJ. A post-mortem <br />study of reduced surface area asymmetry and altered minicolumn <br />spacing in planum temporale in schizophrenia and review of MRI <br />findings. Brain, in press. <br />8 <br />“Tough Guy” <br />9 <br />Research Activities <br />For the past several years, Dr. Clover’s research study has been <br />focused on vaccines and informatics. With this focus in mind, Dr. <br />Clover, along with several UL faculty members, successfully established <br />the Center for Health Hazard Preparedness, which is based in the <br />School of Public Health and Information Sciences. With expertise in <br />immunizations and infectious diseases, Dr. Clover continues to be a <br />published author in medical literature and an invited lecturer at national <br />and international medical meetings. <br />Peer-reviewed Publications <br />Zimmerman RK. Middleton DB. Burns IT. Clover RD. Kimmel SR. <br />Routine vaccines across the life span, 2007. Journal of Family Practice. <br />56(2 Suppl Vaccines):S18-37, C1-3, 2007 Feb. <br />Clover RD. Clinical practice guideline for bronchiolitis: key <br />recommendations. American Family Physician. 75(2):171, 2007 Jan 15. <br />Richard D. Clover, Ph.D. <br />Research Activities <br />We are studying the molecular basis for trafficking of secreted <br />proteins within the cell during regulated secretion. Secretory proteins <br />synthesized in the major salivary glands, including the parotid glands, <br />are primarily stored in dense-core secretory granules and released <br />in response to external stimuli (regulated or stimulated secretion). <br />Parotid salivary proteins are secreted apically, primarily by the regulated <br />secretory pathway. Understanding how sorting occurs in salivary glands <br />would contribute to the correct targeting of therapeutic transgenes. To <br />study the molecular basis for trafficking, we use a proteomics approach <br />to define proteins in the secretory granule membrane, and systems <br />biology approaches to define regulatory pathways. We hope to define <br />the developmental mechanisms that create the secretory pathways. <br />In addition, our laboratory is interested in the regulation of gene <br />transcription in eucaryotic cells. We are investigating the molecular <br />mechanism of action of the zfh family of transcription factors. We <br />have isolated cDNA and genomic clones of the Zfhep/Zfhx1a/ <br />ZEB1 transcription factor. ZEB1 is essential for life as well as T-cell <br />development, craniofacial development, and skeletal patterning. ZEB1 <br />is a SMAD-binding protein, and therefore is part of the TGFbeta family <br />signaling mechanism. Current projects investigate the role of ZEB1 and <br />related genes in early development, and the molecular interactions that <br />underlie those roles. We focus on development of the eye, which has <br />specific defects in ZEB1-mutant mice that mimic birth defects in some <br />human babies. In addition, we are studying the molecular basis for cleft <br />palate in ZEB1 knock-out mice. <br />Grants Funded <br />Role: Principal Investigator <br />Title: Selective Aggregation and Sorting of Salivary Protein <br />Funding Agency: National Institutes of Health, NIDCR <br />Direct Costs Funded: $875,000 <br />Role: Principal Investigator <br />Title: Ocular Defects Caused by TCF8/Zfhx1a Mutation <br />Funding Agency: NIH/ NEI <br />Direct Costs Funded: $275,000 <br />Role: Co-Investigator <br />Title: Oral H. pylori Prevalence in Intellectually/Developmentally <br />Disabled Adults <br />Funding Agency: NIH/NIDCR <br />Direct Costs Funded: $275,000 <br />Douglas Darling, Ph.D. <br />Dean <br />School of Public Health and <br />Information Sciences <br />Associate Vice President for Health <br />Affairs/Health Informatics <br />School of Public Health and <br />Information Sciences <br />Professor <br />Department of Periodontics, <br />Endodontics &amp; Dental Hygiene <br />School of Dentistry <br />Role: Principal Investigator <br />Title: Identifying Periodontal Antigens By Protein Microarray <br />Funding Agency: NIH/NIDCR <br />Direct Costs Funded: $275,000 <br />Role: Co-Investigator; PI Ken Ramos <br />Title: Center for Environmental Genomics and <br />Integrative Biology (CEGIB) <br />Funding Agency: NIH/NIEHS <br />Direct Costs Funded: $3,000,000 <br />Role: Principal Investigator <br />Title: Mathematical Model of Parotid Acinar Differentiation <br />Funding Agency: NIH/NIDCR <br />Direct Costs Funded: $1,900,000 <br />Peer-reviewed Publications <br />S.G. Venkatesh, J. Tan, S.U. Gorr and D.S. Darling (2007) <br />Isoproterenol Increases Sorting Of Parotid Gland Cargo Proteins To <br />The Basolateral Pathway. Am J Physiol Cell Physiol. 293: C558 - C565. <br />PMID: 17537806, PMCID: PMC2084485. <br />Manavella PA, Roqueiro G, Darling DS, and Cabanillas AM. (2007) <br />The ZFHX1A gene is differentially autoregulated by its isoforms. <br />Biochem. Biophys. Res. Commun. 360(3): 621-626. PMID:17610840. <br />doi:10.1016/j.bbrc.2007.06.088 <br />Kitchens DH, Binkley CJ, Wallace DL, Darling DS, (2007) Helicobacter <br />pylori Infection in Intellectually and Developmentally Disabled Persons: <br />A Review. Special Care in Dentistry. 27 (4):127-33, PMID:17972442. <br />Liu Y, Costantino ME, Durango-Montoya D, Darling DS, and Dean <br />DC (2007): The zinc finger transcription factor ZFHX1A is linked to cell <br />proliferation through the Rb/E2F pathway. Biochem. J. 408(1): 79-85. <br />doi:10.1042/BJ20070344. PMID:17655524. PMCID: PMC2049079. <br />Kowase T, Walsh HE, Darling DS, and Shupnik MA (2007) Estrogen <br />Enhances GnRH-Stimulated Transcription of the LH Subunit Promoters <br />via Altered Expression of Stimulatory and Suppressive Transcription <br />Factors. Endocrinology, 148: 6083 – 6091. doi;10.1210/en.2007- <br />0407. PMID:17823254. <br />Liu Y, El-Naggar S, Darling DS, Higashi Y, and Dean DC (2008) <br />Zeb1 links epithelial-mesenchymal transition and cellular senescence. <br />Development 135, 579-588. doi:10.1242/10.1242/dev.007047. <br />PMID: 18192284. <br />Jin JZ, Li Q, Higashi Y, Darling DS, and Ding J (2008) Analysis of <br />Zfhx1a mutant mice reveals palatal shelf contact-independent medial <br />edge epithelial differentiation during palate fusion. Cell and Tissue <br />Research, 333:29-38. doi: 10.1007/s00441-008-0612-x <br />Singh M, Spoelstra NS, Jean A, Howe E, Torkko KC, Clark HR, Darling <br />DS, Shroyer KR, Horwitz KB, Broaddus RR, and Richer JK (2008) <br />ZEB1 expression in type I vs type II endometrial cancers: a marker of <br />aggressive disease. Mod Pathol. 21(7): 912-23. PMID 18487993. <br />Liu Y, Peng X, Tan J, Darling DS, Kaplan HJ, and Dean DC (2008) <br />Zeb1 Mutant Mice as a Model of Posterior Corneal Dystrophy. Invest. <br />Ophthalmol. Vis. Sci., 49: 1843 - 1849. DOI: 10.1167/iovs.07-0789. <br />10 <br />11 <br />Research Activities <br />My research interests include Bioinformatics, Biostatistics, Statistical <br />issues in Population Biology, Statistical Genetics, Infectious Disease <br />Modeling and Survival Analysis. My latest interest is in stochastic <br />modeling of biological systems. In bioinformatics my research <br />includes transcriptomics (microarray data analysis), <br />proteomics (analysis of MALDI-MS, MALDI-MS/MS, SELDI <br />data) and metabolomics. I have generated my own data <br />to detect biomarker of fetal alcohol related disorder. <br />In a nutshell, my research involves high dimensional <br />data analysis using modern multivariate clustering <br />and classification techniques. I am involved in <br />collaborative research with interdisciplinary scientists <br />from Biochemistry, Biology, Public Health and Computer <br />scientists. My research is funded by National Science Foundation and <br />National Institute of Health. <br />Grants Funded <br />Role: Principal Investigator <br />Title: Statistical Peak Detection, Adaptive Classification and Protein- <br />Protein Network Construction Using Mass Spectra <br />Funding Agency: National Science Foundation-Division of <br />Mathematical Sciences <br />Direct Costs Funded: $150,000 <br />Role: Co-Investigator <br />Title: Center for Environmental Genomics and Integrative Biology <br />Funding Agency: NIH/NIEHS <br />Direct Costs Funded: $3,000,000 <br />Susmita Datta, Ph.D. <br />Role: Co-Investigator <br />Title: Pediatric Clinical Proteomics Center <br />Bioinformatics data analysis for multiple <br />proteomics project for pediatric <br />proteomic clinical data. <br />Funding Agency: NIH/NIDDK <br />Direct Costs Funded: $3,000,000 <br />Role: Co-Investigator <br />Title: Urinary Proteomics in Aminoglycoside- <br />Treated Newborns <br />Funding Agency: NICHD <br />Direct Costs Funded: $125,000 <br />Role: Principal Investigator Subcontract <br />Title: Assessment of Pathway Design through Multi-level Modeling <br />and Experimentation <br />Funding Agency: National Science Foundation <br />Direct Costs Funded: $692,460 <br />Peer-reviewed Publications <br />Datta, S., Le-Rademacher, J. and Datta, S. (2007). Predicting patient <br />survival from microarray data by accelerated failure time modeling using <br />partial least squares and LASSO, Biometrics, 63, 259-271. <br />Datta, S., Datta, S., Parrish, R. S. and Thompson, C. M. (2007). <br />Microarray data analysis. In Computational Methods in Biomedical <br />Research, R. Khatree and D. Naik, eds., Chapman &amp; Hall/CRC <br />Biostatistics Series, Volume 24, 1-43. <br />Boratyn, G. M., Datta, S. and Datta, S. (2007). Incorporation of <br />biological knowledge into distance for clustering genes. Bioinformation, <br />1, 396-405. <br />Pihur, V., Datta, S. and Datta, S. (2007). Weighted rank aggregation of <br />cluster validation measures: A Monte Carlo cross-entropy approach. <br />Bioinformatics, 23, 1607-1615. <br />Pihur, V., Datta, S. and Datta, S. (2008). Finding cancer genes through <br />meta-analysis of microarray experiments: Rank aggregation via <br />the cross entropy algorithm. Genomics, to appear. doi:10.1016/j. <br />ygeno.2008.05.003 <br />Associate Professor <br />Department of Bioinformatics and <br />Biostatistics <br />School of Public Health and <br />Information Sciences <br />12 <br />Pihur, V., Datta, S. and Datta, S. (2007). Understanding Chronic <br />Fatigue Syndrome (CFS) from CAMDA data: A systems biology <br />approach. Proceedings of CAMDA 2007, full paper, online @ <br />http://camda.bioinfo.cipf.es/camda07/agenda/detailed.html. <br />Pihur, V., Brock, G., Datta, S. and Datta, S. (2008). Cluster validation <br />for microarray data: An appraisal. In Multivariate Statistical Methods, <br />( A. SenGupta, ed), ISI Platinum Jubilee series, Vol 5, World Scientific <br />Press, to appear (2008). <br />Brock, G., Pihur, V., Datta, S. and Datta, S. (2008). clValid , an R <br />package for cluster validation. Journal of Statistical Software, 25, 4. <br />Pihur, V., Datta, S. and Datta, S. (2008). Reconstruction of genetic <br />association networks from microarray data: A partial least squares <br />approach. Bioinformatics, 24, 561-568. <br />Datta, S., Turner, D., Singh, R., Ruset, B., Pierce, W. M., and <br />Knudsen, T. B. (2008). Fetal alcohol syndrome in mice detected <br />through proteomics screening of the amniotic fluid. Birth Defects <br />Research Part A: Clinical and Molecular Teratology, 82, 177-186. <br />Datta, S. and Pihur, V. (2008). Feature selection and machine <br />learning with mass spectrometry data, R. Matthiesen, ed., In Clinical <br />Proteomics: Methods, Applications and Tools, Humana Press, to <br />appear. <br />Research Activities <br />The research in Dr. Ding’s laboratory is aiming to elucidate the <br />molecular basis of congenital diseases through understanding the <br />molecular pathways and genetic programs that control fundamental <br />embryonic processes such as axis formation, cardiac development, <br />neural induction and placenta formation. On going studies address <br />TGF-ßs and Nodal signaling pathways during holoprosencephaly <br />(HPE) and other craniofacial malformation such as cleft palate using <br />genetically manipulated mouse models. We have also addressed the <br />formation of the first and second heart fields and dynamic relationship <br />between the two heart fields during mouse cardiac morphogenesis. In <br />addition to the mouse genetic approach, we have also established the <br />Zebrafish model system in the laboratory aiming to dissect the details <br />of the pathways controlling the above developmental processes. <br />Grants Funded <br />Role: Principal Investigator <br />Title: Regulation of Nodal signaling in holoprosencephaly <br />Funding Agency: National Institutes of Health <br />Direct Costs Funded: $1,125,000 <br />Role: Principal Investigator <br />Title: Regulation of Nodal signaling in holoprosencephaly <br />Funding Agency: National Institutes of Health <br />Direct Costs Funded: $482,958 <br />Peer-reviewed Publications <br />Jin JZ, Li Q, Higashi Y, Darling DS, Ding J. Analysis of Zfhx1a mutant <br />mice reveals palatal shelf contact-independent medial edge epithelial <br />differentiation during palate fusion. Cell Tissue Res. 33: 29-38 (2008) <br />Jixiang Ding, Ph.D. <br />Assistant Professor <br />Departments of Molecular, Cellular &amp; <br />Craniofacial Biology <br />School of Dentistry <br />E#2: double in situ hybridization <br />of the Mlc2a gene (red) and <br />the Cripto gene (brown) in wild <br />type embryo showing that Cripto <br />expression is located within the <br />developing heart region <br />Research Activities: <br />Dr. Epstein’s primary interests are in the causes and complications of <br />diabetes. Dr. Epstein and his research group particularly focus on the <br />complications of diabetic cardiomyopathy and nephropathy. They also <br />investigate the loss of beta cell function that occurs with autoimmune <br />reactions and disrupted sleep cycles. <br />Dr. Epstein was the first to demonstrate that blood glucose is <br />maintained by a single reaction in the pancreatic beta cell. He has <br />developed the most accurate model of diabetes for study of diabetic <br />nephropathy in rodents. Dr. Epstein has shown that antioxidants can <br />protect the heart from the chronic impairment produced by diabetes. <br />He has also demonstrated that a specific cardiac metabolite controls <br />cardiac insulin sensitivity. Other results from his laboratory demonstrate <br />that antioxidant protection of one type of kidney cell, the podocyte, <br />prevents albuminuria in diabetic <br />Grants Funded: <br />Role: Principal Investigator <br />Title: Podocytes and Oxidative Stress in Diabetic Kidney <br />Funding Agency: NIH/NIDDK <br />Direct Costs Funded: $250,000 <br />Role: Principal-Investigator <br />Title: Prolonged Diabetic Damage to Cardiac Mitochondria <br />Funding Agency: NIH <br />Direct Costs Funded: $244,000 <br />Role: Principal-Investigator <br />Title: Podocyte Specific Antioxidant Protection in Diabetic Nephropathy <br />Funding Agency: Juvenile Diabetes Research Foundation <br />Direct Costs Funded: $60,000 <br />Role: Principal-Investigator <br />Title: Antioxidant Transgenes In Diabetic Cardiomyopathy <br />Funding Agency: NIH/NHLBI <br />Direct Costs Funded: $200,000 <br />Role: Principal-Investigator <br />Title: Altered Glucose Homeostasis by Sleep Impairment <br />Funding Agency: NIH/NHLBI <br />Direct Costs Funded: $225,000 <br />Professor <br />Department of Pediatrics <br />Department of Pharmacology &amp; <br />Toxicology <br />School of Medicine <br />13 <br />Role: Collaborator <br />Title: B-cells in Pups of Mild and Severe <br />STZ Diabetic Mothers; Antioxidant Protection <br />Funding Agency: NIH <br />Direct Costs Funded: $200,000 <br />Role: Collaborator <br />Title: Training Program in Transplantation <br />Funding Agency: NIH/NHLBI <br />Direct Costs Funded: $823,577 <br />Role: Collaborator <br />Title: UofL Environmental Health Sciences Training Program <br />Funding Agency: NIH/NIEHS <br />Peer-reviewed Publications: <br />Ai, J.; Epstein, P. N.; Gozal, D.; Yang, B.; Wurster, R.; Cheng, Z. <br />J. Morphology and topography of nucleus ambiguus projections to <br />cardiac ganglia in rats and mice. Neuroscience 149:845-860; 2007. <br />Paul N. Epstein, M.D. <br />14 <br />Donthi, R. V.; Epstein, P. N. Altering and analyzing glucose metabolism <br />in perfused hearts of transgenic mice. Methods Mol Med 139:151-161; <br />2007. <br />Han, J.; Xu, J.; Long, Y. S.; Epstein, P. N.; Liu, Y. Q. Rat maternal <br />diabetes impairs pancreatic beta-cell function in the offspring. Am J <br />Physiol Endocrinol Metab 293:E228-236; 2007. <br />Song, Y.; Du, Y.; Prabhu, S. D.; Epstein, P. N. Diabetic <br />Cardiomyopathy in OVE26 Mice Shows Mitochondrial ROS Production <br />and Divergence Between In Vivo and In Vitro Contractility. Rev.Diabet. <br />Stud. 4:159-168; 2007. <br />Zaruba, R. A.; Epstein, P. N.; Carr, P. A. Hyperglycemia alters enzyme <br />activity and cell number in spinal sensory ganglia. J Brachial.Plex. <br />Peripher.Nerve Inj. 2:11; 2007. <br />Gu, H.; Epstein, P. N.; Li, L.; Wurster, R. D.; Cheng, Z. J. Functional <br />changes in baroreceptor afferent, central and efferent components of <br />the baroreflex circuitry in type 1 diabetic mice (OVE26). Neuroscience <br />152:741-752; 2008. <br />Teiken, J. M.; Audettey, J. L.; Laturnus, D. I.; Zheng, S.; Epstein, P. N.; <br />Carlson, E. C. Podocyte loss in aging OVE26 diabetic mice. Anat Rec <br />(Hoboken) 291:114-121; 2008. <br />Wang, Q.; Donthi, R. V.; Wang, J.; Lange, A. J.; Watson, L. J.; Jones, <br />S. P.; Epstein, P. N. Cardiac phosphatase-deficient 6-phosphofructo- <br />2-kinase/fructose-2,6-bisphosphatase increases glycolysis, <br />hypertrophy, and myocyte resistance to hypoxia. Am J Physiol Heart <br />Circ Physiol 294:H2889-2897; 2008. <br />Xu, J.; Han, J.; Long, Y. S.; Epstein, P. N.; Liu, Y. Q. The role of <br />pyruvate carboxylase in insulin secretion and proliferation in rat <br />pancreatic beta cells. Diabetologia 51:2022-2030; 2008. <br />Xu, J.; Han, J.; Long, Y. S.; Lock, J.; Weir, G. C.; Epstein, P. N.; Liu, <br />Y. Q. Malic enzyme is present in mouse islets and modulates insulin <br />secretion. Diabetologia; 51:2281-2289; 2008. <br />Zheng, S.; Carlson, E. C.; Yang, L.; Kralik, P. M.; Huang, Y.; Epstein, P. <br />N. Podocyte-Specific Overexpression of the Antioxidant Metallothionein <br />Reduces Diabetic Nephropathy. J Am Soc Nephrol; 19:2077-2085; <br />2008. <br />Yang, L.; Zheng, S.; Epstein, P. N. Metallothionein over-expression in <br />podocytes reduces adriamycin nephrotoxicity. Free Radical Research; <br />2008 In Press. <br />David W. Powell, Clinton C Bertram, Timothy D. Cummins, Michelle <br />T. Barati, Shirong Zheng, Paul N. Epstein and Jon B. Klein: Renal <br />Tubulointerstiti al Fibrosis in OVE26 Type 1 Diabetes Mice. In Press <br />2008. <br />Jianxing Xu, Yun-Shi Long, David Gozal and Paul N. Epstein Beta Cell <br />Death and Proliferation after Intermittent Hypoxia: Role of Oxidative <br />Stress . Free Radical Biol Med In Press 2008. <br />Research Activities <br />Dr. Gozal’s research interests include bench to bedside approaches <br />to the study of pediatric sleep disorders and respiratory control <br />using sophisticated techniques such as gene arrays and protein chip <br />technologies, and also more specific studies on cellular and animal <br />models of sleep-disordered breathing. In addition, Dr. Gozal’s research <br />program conducts clinical, physiological, and epidemiological studies <br />on sleep in children. <br />Grants Funded <br />Role: Principal Investigator <br />Title: Neurocognitive Function in Snoring Children <br />Funding Agency: National Heart Lung and Blood Institute <br />Direct Costs Funded: $1,500,000 <br />Role: Principal Investigator, University of Louisville Site <br />Title: Tonsillectomy and Adenoidectomy in Children with Sleep <br />Disordered Breathing <br />Funding Agency: National Heart Lung and Blood Institute, Multi- <br />Center Study <br />Direct Costs Funded: $200,000 (UofL site) <br />Role: Co-Investigator <br />Title: Sleep and Sleep Disorders In ChildrenFunding Agency: NIH, <br />National Heart Lung and Blood Institute <br />Direct Costs Funded: $1,250,000 <br />Role: Principal Investigator <br />Title: Oxidative Stress in a Murine Model of Sleep Apnea <br />Funding Agency: National Heart Lung and Blood Institute <br />Direct Costs Funded: $1,250,000 <br />David Gozal <br />Peer-reviewed Publications <br />O’Brien LM, Gozal D. Potential usefulness of non-invasive autonomic <br />monitoring in recognition of arousals in normal healthy children. J. Clin. <br />Sleep. Med. 2007; 3:41-47. <br />Montgomery-Downs HE, Gozal D. Toddler behavior after <br />polysomnography: effects of unintended partial sleep deprivation. Sleep <br />2006; 29:1282-1287. <br />Molfese V, Beswick J, Molnar A, Jacobi-Vessels J, Gozal D. The <br />impacts of sleep duration, problem behaviors and health status on letter <br />knowledge in pre-kindergarten children. Child Health and Education: An <br />Interdisciplinary Journal. 2007; 1:41-53. <br />O’Brien LM, Holbrook CR, Jones VF, Gozal D. Ethnic differences in <br />periodic leg movements in children. Sleep Med 2007;8:240-246. <br />Tauman R, Serpero LD, Sans Capdevila O, O’Brien LM, Goldbart <br />AD, Kheirandish-Gozal L, Gozal D. Adipokines in children with sleepdisordered <br />breathing. Sleep 2007; 30:443-449. <br />Tauman R, O’Brien LM, Gozal D. Hypoxemia and obesity modulate <br />plasma C-reactive protein and interleukin 6 levels in snoring children. <br />Sleep &amp; Breathing 2007; 11;77-84. <br />Professor <br />Department of Pediatrics <br />School of Medicine <br />Director <br />Kosair Children’s Hospital Research <br />Institute <br />Distinguished University Scholar <br />Mediano O, Barcelo A, de la Pena M, Gozal D, Agusti A, Barbe F. <br />Sleepiness and polysomnographic variables in sleep apnea patients. Eur. <br />J. Resp. Med. 2007; 30:1396-1399. <br />De la Pena Bravo M, Serpero LD, Barcelo A, Barbe F, Agusti A, Gozal <br />D. Inflammatory proteins in patients with obstructive sleep apnea with <br />and without daytime sleepiness. Sleep &amp; Breathing 2007; 11:177-185. <br />Dayyat E, Maarafeya MAM, Sans Capdevila O, Kheirandish-Gozal L, <br />Montgomery-Downs HE, Gozal D. Nocturnal body position in sleeping <br />children with and without obstructive sleep apnea. Pediatr. Pulmonol. <br />2007; 42:374-379. <br />Kheirandish-Gozal L, Miano S, Bruni O, Ferri R, Pagani J, Villa MP, Gozal <br />D. Reduced NREM sleep instability in children with sleep-disordered <br />breathing. Sleep 2007; 30:450-457. <br />Ai J, Gozal D, Li L, Wead WB, Chapleau MW, Wurster R, Yang B, Li H, <br />Liu R, Cheng ZJ. Degeneration of vagal efferent axons and terminals in <br />cardiac ganglia of aged rats. J Comp Neurol. 2007;504:74-88. <br />Lin M, Liu R, Gozal D, Wead WB, Chapleau MW, Cheng ZJ. Chronic <br />intermittent hypoxia impairs baroreflex control of heart rate but enhances <br />heart rate responses to vagal stimulation in anesthetized mice. Am. J. <br />Physiol. (Heart and Circul. Physiol.) 2007; 293(2):H997-H1006. <br />Gozal D, McLaughlin Crabtree V, Sans Capdevila O, Witcher LA, <br />Kheirandish-Gozal L. C reactive protein, obstructive sleep apnea, and <br />cognitive dysfunction in school-aged children. Am J Respir Crit Care <br />Med 2007; 176:188-193. <br />Gozal D, Sans Capdevila O, Kheirandish-Gozal L, McLaughlin Crabtree <br />V. Apolipoprotein E e4 allele, neurocognitive dysfunction, and obstructive <br />sleep apnea in school-aged children. Neurology 2007; 69:243-249. <br />Chi L, Ke Y, Luo C, Gozal D, Liu R. Depletion of reduced glutathione <br />enhances motor neuron degeneration in vitro and in vivo. Neuroscience. <br />2007; 144:991-1003. <br />Lin S, Walker J, Xu L, Gozal D, Yu J. Behaviors of pulmonary sensory <br />receptors during development of acute lung injury in the rabbit. Exp <br />Physiol. 2007; 92:749-755. <br />Montgomery-Downs HE, Crabtree VM, Sans Capdevila O, Gozal D. <br />Infant feeding methods and childhood sleep-disordered breathing. <br />Pediatrics 2007; 120(5):1030-1035. <br />Hambrecht VS, Vlisides PE, Row BW, Gozal D, Baghdoyan HA, Lydic <br />R. Cholinergic and opioid activation of G proteins in rat hippocampus: <br />modulation by hypoxia. Hippocampus 2007; 17(10):934-942. <br />Soukhova-O’Hare GK, Schmidt MH, Nozdrachev AD, Gozal D. A novel <br />mouse model for assessment of sexual function. Physiol Behav 2007; <br />91:535-543. <br />Goldbart AD, Mager E, Veling MC, Goldman JL, Kheirandish-Gozal <br />L, Serpero LD, Piedimonte G, Gozal D. Neurotrophins and tonsilllar <br />hypertrophy in children with obstructive sleep apnea. Pediatr. Res. 2007; <br />62(4):489-494. <br />Redline S, Budhiraja R, Kapur V, Marcus CL, Mateika JH, Mehra R, <br />Parthasarthy S, Somers VK, Strohl KP, Sulit LG, Gozal D, Wise MS, <br />Quan SF. The scoring of respiratory events in sleep: reliability and validity. <br />J Clin Sleep Med 2007; 3:169-200. <br />Grigg-Damberger M, Gozal D, Marcus CL, Quan SF, Rosen CL, Chervin <br />RD, Wise M, Picchietti DL, Sheldon SH, Iber C. The visual scoring of <br />sleep and arousal in infants and children. J. Clin Sleep Med. 2007; 3:201- <br />240. <br />Zhang SXL, Searcy TR, Wu Y, Gozal D, Wang Y. Tissue-specific <br />expression of mouse monocarboxylate transporter 2 is mediated by <br />alternative promoters. Physiol Genomics 2007; 32(1):95-104. <br />Gozal D, Kheirandish-Gozal L, Serpero LD, Sans Capdevila O, Dayyat <br />E. Obstructive sleep apnea and endothelial function in school-aged <br />non-obese children: effect of adenotonsillectomy. Circulation 2007; <br />116(20):2307-2314. <br />16 <br />17 <br />Ai J, Epstein PN, Gozal D, Yang B, Wurster R, Cheng ZJ. Nucleus <br />ambiguus projections to cardiac ganglia of mice and rats: morphology <br />and topography. Neuroscience 2007; 142(2):163-168. <br />Gu H, Lin M, Liu J, Gozal D, Scrogin KE, Wurster R, Chapleau MW, <br />Cheng ZJ. Functional changes in baroreceptor afferent, central, and <br />efferent components of the baroreflex circuitry in anesthetized F344 <br />young-adult rats following chronic intermittent hypoxia. Am. J. Physiol. <br />(Heart and Circul. Physiol.) 2007; 293(5):H2809-H2818. <br />Shan X, Chi L, Ke Y, Luo C, Qian SY, St Clair D, Gozal D, Liu R. <br />Manganese superoxide dismutase protects mouse cortical neurons from <br />chronic intermittent hypoxia-mediated oxidative damage. Neurobiol Dis. <br />2007; 28(2):206-215. <br />Kheirandish-Gozal L, Sans Capdevila O, Kheirandish E, Gozal D. <br />Elevated liver enzymes in children at risk for obstructive sleep apnea. <br />Chest 2008; 133:92-99. <br />Sans Capdevila O, Dayyat E, Kheirandish-Gozal L. Gozal D. Prevalence <br />of epileptiform activity in healthy children during sleep. Sleep Med 2008; <br />9(3):303-309. <br />Gozal D, Serpero LD, Sans Capdevila O, Kheirandish-Gozal L. Systemic <br />inflammation in non-obese children with obstructive sleep apnea. Sleep <br />Med. 2008; 9(3):254-259. <br />Gozal D, Kheirandish-Gozal L, Sans Capdevila O, Dayyat E, Kheirandish <br />E. Prevalence of recurrent otitis media in habitually snoring school-aged <br />children. Sleep Med 2008; 9(5):549-54. <br />Li RC, Morris MW, Lee SK, Pouranfar F, Wang Y, Gozal D. Neuroglobin <br />protects PC12 cells against oxidative stress. Brain Res. 2008; 1190:159- <br />166. <br />Trochet D, De Ponctual L, Straus C, Gozal D, Trang H, Landrieu P, <br />Munnich A, Lyonnet S, Gaultier C, Amiel. Germinal mutation and somatic <br />mosaic of phox2b in late onset central hypoventilation syndrome. Am J <br />Resp Crit Care Med 2008; 177(8):906-911. <br />Gozal D, Kheirandish-Gozal L. Cardiovascular morbidity in obstructive <br />sleep apnea: Oxidative stress, inflammation, and much more. Am J Resp <br />Crit Care Med. 2008; 177(4):369-375. <br />Sans Capdevila O, Kheirandish-Gozal L, Dayyat E, Gozal D. Pediatric <br />obstructive sleep apnea: Complications, management, and long-term <br />outcomes. Proc Am Thor Soc 2008; 5(2):274-282. <br />\Carvalho Bos S, Gomes A, Clemente V, Marques M, Pereira AT, Maia <br />B, Soares MJ, Cabral AS, Macedo A, Gozal D, Azevedo MH. Sleep, <br />behavioral, and emotional problems in children: a population-based <br />study. Sleep Med 2008; (in press) <br />Khalyfa A, Sans Capdevila O, Boazza M, Serpero LD, Kheirandish-Gozal <br />L, Gozal D. Genome-wide gene expression profiling in children with <br />obstructive sleep apnea. Sleep Med 2008; (in press) <br />Wu W, Nilesh DB, Strollo PJ, Kovkarova-Naumovski E, Ryter SW, Reeves <br />SR, Dayyat E, Wang Y, Choi AMK, Gozal D, Kaminski N. Network <br />analysis of temporal effects of intermittent- and sustained hypoxia on rat <br />lungs. Physiol Genomics 2008; (in press) <br />Lin L, Ai J, Chapleau MW, Liu R, Gozal D, Wead WB, Wurster R, Cheng <br />ZJ. Structural remodeling of nucleus ambiguus projections to cardiac <br />ganglia following chronic intermittent hypoxia in C57BL/6J mice. J. <br />Comp. Neurol. 2008; 509(1):103-117. <br />Gozal D, Sans Capdevila O, McLaughlin Crabtree V, Serpero LD, <br />Witcher LA, Kheirandish-Gozal L. Plasma insulin growth factor 1 levels <br />and cognitive dysfunction in school-aged children with obstructive sleep <br />apnea. Sleep Medicine 2008 (in press) <br />Monchanin G, Serpero LD, Connes P, Tripette J, Wouassi D, Francina <br />A, Massarelli R, Gozal D, Thiriet P, Martin C. Plasma levels of adhesion <br />molecules ICAM-1 and VCAM-1 in athletes with sickle cell trait with or <br />without a-thalassemia during endurance exercise and recovery. Clin. <br />Hemorheology and Microcirc. 2008; (in press) <br />Soukhova-O’Hare GK, Ortines RV, Gu Y, Nozdrachev AD, Prabhu <br />SD, Gozal D. Postnatal intermittent hypoxia and developmental <br />programming of hypertension in SHR: Role of ROS and L-Ca2+ <br />channels. Hypertension 2008; 52(1):156-162. <br />18 <br />Kheirandish-Gozal L, Gozal D. Intranasal budesonide treatment in <br />children with mild obstructive sleep apnea syndrome. Pediatrics 2008; <br />122(1):e149-155. <br />Gozal D, Sans Capdevila O, Kheirandish-Gozal L. Metabolic alterations <br />and systemic inflammation in obstructive sleep apnea among nonobese <br />and obese pre-pubertal children. Am J Resp Crit Care Med 2008; <br />177(10):1142-1149. <br />Zhang SXL, Miller JJ, Stolz D, Serpero LD, Zhao W, Gozal D, Wang <br />Y. Type I epithelial cells are the main target of whole-body hypoxic <br />preconditioning in the lung. Am J. Resp. Cell. Mol. Biol. 2008; (in press) <br />Yan B Soukhova-O’Hare GK, Li L, Lin Y, Gozal D, Wead WB, Wurster <br />RD, Cheng ZJ. Attenuation of heart rate control and neural degeneration <br />in nucleus ambiguus (NA) following chronic intermittent hypoxia (CIH) in <br />young adult Fischer 344 rats. Neuroscience 2008; 153(3):709-720. <br />Sans Capdevila O, Crabtree VM, Kheirandish-Gozal L, Gozal D. <br />Increased morning brain natriuretic peptide levels in children with <br />nocturnal enuresis and sleep disordered breathing: A community-based <br />study. Pediatrics 2008; 121(5):e1208-1214. <br />Roure N, Mediano O, Duran J, Garcia Rio J, de la Peña M, Capote F, <br />Teran J, Masa JF, Alonso ML, Corral J, Sánchez-Armengol A, Martinez C, <br />Barceló A, Gozal D, Barbé F. Daytime sleepiness and polysomnography <br />in obstructive sleep apnoea patients. Sleep Medicine 2008 (in press) <br />Roure N, Gomez S, Mediano O, Duran J, de la Peña M, Capote F, <br />Teran J, Masa JF, Gozal D, Barbé F. Influencia del sexo en las variables <br />clínicas y polisomnográficas del síndrome de apneas del sueño. Arch <br />Bronconeumol. 2008;44(11):607-10 <br />Soukhova-O’Hare GK, Shah ZA, Lei Z, Nozdrachev AD, Rao CV, Gozal <br />D. Erectile dysfunction in a murine model of sleep apnea. Am J Resp Crit <br />Care Med 2008; 178(6):644-650. <br />Reeves SR, Simakajornboon N, Gozal D. The role of nitric oxide in the <br />neural control of breathing. Respir. Physiol. &amp; Neurobiol. 2008; (in press) <br />Serpero LD, Kheirandish-Gozal L, Dayyat E, Goldman Jl, Kim J, Gozal <br />D. A mixed cell culture model for assessment of proliferation in tonsillar <br />tissues from children with obstructive sleep apnea or recurrent tonsillitis. <br />Laryngoscope 2008 (in press) <br />Associate Professor <br />Department of Pediatrics <br />Department of Pharmacology &amp; Toxicology <br />School of Medicine <br />Evelyne Gozal, Ph.D. <br />Research Activities: <br />Oxygen deprivation affecting cellular survival frequently occurs in <br />cerebrovascular disorders, pulmonary diseases, sleep apnea, and <br />nervous system injury such as brain or spinal cord <br />traumatic injury. All these disorders are accompanied <br />by excessive neuronal cell loss associated with <br />sustained or intermittent restriction in oxygen <br />supply to the neural tissue. A succession of <br />events leads to pathological consequences, <br />with the primary insult, <br />followed by a secondary <br />wave of injury mediated by <br />various pathophysiological <br />mechanisms, involving both <br />necrosis and apoptosis, <br />and expanding the primary <br />damage. Hypoxia induces <br />stress-related pathways promoting <br />angiogenesis, glycolysis, growth factors signaling, <br />genetic instability, tissue invasion, oxidative stress <br />and apoptosis, as part of a neural tissue stress <br />response. The balance of these pathways may determine cellular fate <br />and disease outcome. Exposure to stress induces the expression <br />of a highly conserved family of proteins, the heat shock proteins, <br />a universal mechanism of cellular defense in various organisms. <br />Constitutively expressed Hsps function as molecular chaperones and <br />participate in protein synthesis, folding, and protein transport. During <br />cellular stress, they play a role in preventing aggregation of damaged <br />proteins, refolding proteins, or targeting them to degradation and <br />may also prevent apoptosis by binding pro-apoptotic proteins and <br />inhibiting apoptosome formation and caspase activation. Alternatively, <br />in response to increased accumulation of misfolded or ubiquitinated <br />proteins, Hsps can induce apoptosis to remove dysfunctional cells by <br />releasing the bound pro-apoptotic proteins. Thus, understanding the <br />modulation of hypoxia-induced pro-and anti-apoptotic pathways in <br />neurons and supporting tissue, and their modulation by stress-induced <br />proteins may provide novel therapeutic strategies for diseases involving <br />insufficient apoptosis, such as cancer and autoimmune disease <br />or those associated with increased apoptosis such as ischemia, <br />neurodegenerative diseases, or traumatic injury. Therapeutic strategies <br />interfering with the signaling events triggered in response to hypoxia/ <br />ischemia may prevent delayed injury and improve recovery. <br />Various projects currently under investigation in our laboratory include: <br />• Cellular models in intermittent and sustained hypoxia. <br />• Hypoxia-induced stress response: role of heat shock proteins in <br />the regulation of survival kinases. <br />• Protein-protein interactions in signaling complexes induced by <br />hypoxia. <br />• Signal transduction pathways underlying cellular metabolism and <br />adaptation to hypoxia/ischemia and oxidative stress. <br />• The role of stress response and heat shock protein induction <br />in the modulation of cellular survival after spinal cord injury, and <br />prevention of secondary traumatic injury. <br />Grants Funded: <br />Role: Principal Investigator Project 1 <br />Title: Mechanisms of Plasticity and repair after SCI, Project 1: Heat <br />shock proteins in spinal cord neural survival <br />Funding Agency: NIH/ National Center for Research Resources <br />Direct Costs Funded: $ 902,020 <br />Role: Co-Investigator <br />Title: Modulation of Neutrophil Apoptosis by Akt-Hsp27 Signalosome <br />Funding Agency: National Institute of Allergy and Infectious Diseases <br />Direct Costs Funded: $ 900,000 <br />Peer-reviewed Publications: <br />Machaalani R, Arlotto M, Waters KA, Gozal E, Berger F, Dematteis M. <br />A novel method of tissue collection and storage: Validation using SELDI <br />–TOF MS analysis. Clin. Chem.53 (7): 1387-1389 (2007). <br />Dematteis M, Julien C, , Guillermet C, Sturm N, Lantuejoul S, Mallaret <br />M, Levy P, Gozal E. Intermittent hypoxia induces Early functional and <br />structural cardiovascular remodeling in mice. Am. J. Resp. Crit. Care <br />Med. 177: 227-235, (2008). <br />Research Activities: <br />A quarter of a million babies—3% of all infants born in the US each <br />year—have some mental or physical defect that is evident at birth. <br />Since the causes of nearly all birth defects are largely unknown, <br />research into molecular regulatory mechanisms responsible for normal <br />embryogenesis provides the framework for investigations into the <br />etiology of abnormal embryonic development. <br />Craniofacial malformations occur with a frequency of 1 in 600 live births <br />annually in the United States. Our previous studies have provided <br />substantial evidence supporting the premise that various cellular <br />signal transduction pathways interact to regulate cell proliferation and <br />cell differentiation in embryonic craniofacial tissue. Such interactions <br />represent the underpinnings of a complex and delicately balanced <br />developmental system where morphogenesis and cellular differentiation <br />of the craniofacial region are mediated by the sequential expression of <br />molecular signals. Our studies dealing with molecular analyses of gene <br />function in the embryo—utilizing the developing craniofacial region—are <br />designed to provide definition and clarification of developmental <br />signaling pathways critical for normal embryogenesis as well as <br />identification of foci for perturbation and attendant fetal abnormalities. <br />Current studies—selected specifics outlined briefly below—are <br />designed to identify means by which signal transduction pathways, <br />known to be critical in development of the craniofacial region, regulate <br />gene expression and embryonic development. <br />Overview of selected laboratory investigatory areas: <br />• microRNAs &amp; epigenetic regulation of craniofacial development. <br />Robert M. Greene, Ph.D. <br />They grow up <br />so quickly <br />Professor and Chair <br />Department of Molecular, Cellular &amp; <br />Craniofacial Biology <br />School of Dentistry <br />Director <br />Birth Defects Center <br />Distinguished University Scholar <br />19 <br />• Transcriptional coactivators and craniofacial &amp; neural tube <br />development. <br />• Transcriptional coactivators and folate-mediated development. <br />• Cigarette smoke-induced intrauterine growth retardation &amp; <br />postnatal cognitive deficits. <br />• TGFß/Smad signaling mechanisms in embryonic craniofacial <br />development. <br />Grants Funded: <br />Role: Principal Investigator <br />Title: Transcriptional Coactivators and Pregnancy Outcomes <br />Funding Agency: NIH (NICHD) <br />Direct Costs Funded: $1,321,365 <br />Role: Principal Investigator <br />Title: Nutritional Epigenetics and Orofacial Development <br />Funding Agency: NIH <br />Direct Costs Funded: $900,000 <br />Role: Principal Investigator <br />Title: Molecular Determinants of Developmental Defects <br />Funding Agency: NCRR Center for Biomedical Research Excellence <br />Direct Costs Funded: $12,072,292 <br />Role: Principal Investigator <br />Title: Birth Defects Center Postdoctoral <br />Fellowship <br />Funding Agency: Kosair Charities <br />Direct Costs Funded: $45,000 <br />Peer-Reviewed Publications: <br />Singh S, Yin X, Mukhopadhyay P, <br />Pisano MM and Greene RM. Mitogen <br />activated protein kinase signaling <br />pathways in developing orfacial tissue. <br />Birth Defects Research, Part A: Clinical <br />and Molecular Teratology 79:35-44 <br />(2007). PMID: 17177285 <br />Bhatacherjee V, Mukhopadhyay P, Singh S, Johnson C, Philipose J, <br />Warner C, Hackmiller R, Greene RM and Pisano MM. Neural crest <br />and mesoderm lineage-dependent gene expression in developing <br />orofacial tissue. Differentiation 75:463-477 (2007). PMID: 17286603 <br />Warner D, Horn K, Mudd L, Webb CL, Greene RM, Pisano MM. <br />PRDM16/MEL1: A novel Smad binding protein expressed in murine <br />embryonic orofacial tissue. Biochimica Biophysica Acta – Molecular <br />Cell Research 1773:814-820 (2007). PMID: 17467076 <br />Warner DR, Greene RM, Pisano MM. Target Assessment-PRDM16 <br />(MEL1). Targeted Proteins Database (TPdb) (available on-line) (2008). <br />Greene RM, Pisano MP. Perspectives in orofacial cleft research II: <br />Molecular Mechanisms. In: Comprehensive Cleft Care, Edit. Losee JE, <br />Kirschner RE., McGraw-Hill (accepted for publication) (2008). <br />Mukhopadhyay P, Webb C, Warner D, Greene RM, Pisano, MM. BMP <br />signaling dynamics in embryonic orofacial tissue. J Cellular Physiol <br />216:771-779 (2008). PMID: 18446813 <br />Esposito ER, Horn KH, Greene RM, Pisano MM. An animal model <br />of cigarette smoke-induced in utero growth retardation. Toxicology <br />246:193-202 (2008). PMID: 18316152 <br />Horn K, Horn KH, Esposito ER, Greene RM, Pisano MM. The effect <br />of cigarette smoke exposure on developing folate binding protein-2 <br />null mice. Reproductive Toxicology 26:203-209. <br />Warner DR, Smith HS, Webb CL, Greene RM, Pisano MM. <br />Expression of Wnts in the developing murine secondary palate. <br />Internat J Develop Biol (accepted for publication). <br />Bhatacherjee V, Horn K, Singh S, Webb CL, Pisano MM, <br />Greene, RM. CBP/p300 and associated transcriptional <br />coactivators exhibit distinct expression patterns during <br />murine craniofacial and neural tube development. Internat J <br />Develop Biol - (accepted for publication). <br />Why can’t I shave? <br />20 <br />Research Activities: <br />The research in the laboratory continued to focus on the mechanisms <br />and genes responsible for two forms of congenital stationary <br />night blindness (CSNB). Mice deficient in transmission between <br />photoreceptors and second order neurons were analyzed. Mutations <br />in the alpha -1F subunit of voltage dependent calcium channels <br />(Cacn1af) and the metabotropic glutamate receptor 6 (Grm6) subunit <br />were characterized. Mutations in the Cacn1af subunit result in the <br />dendrites of post synaptic neurons extending abnormally, while the <br />retinal morphology of the Grm6 mutant mice is normal. In a third model <br />of CSNB, the nob mouse, studies showed that there is abnormal <br />development resulting in spontaneous bursting of retinal ganglion cells. <br />These mice also fail to form center surround organization of retinal <br />ganglion cells, which is thought to be important in vision. Transgenic <br />rescue of the phenotype of the nob mouse by expression of a <br />EYFP:nyctalopin fusion protein, showed that the nyctalopin was only <br />required at the first synapse to fully restore vision. The availability of this <br />line of mice should allow the function of nyctalopin to be determined. <br />A second project has established an international zebrafish mutant <br />mapping resource. This facility identified the gene responsible for <br />17 mutant lines of fish and provided chromosomal locations for <br />an additional 34 to investigators world wide. This facility is greatly <br />increasing the rate at which mutant zebrafish genes are identified. <br />Grants Funded: <br />Role: Principal Investigator <br />Title: Isolation of congenital stationary night blindness gene <br />Funding Agency: NIH <br />Direct Costs Funded: $286,573 <br />Role: Collaborator (Mervis PI) <br />Title: Genotype/phenotype correlations in Williams Syndrome <br />Funding Agency: NIH <br />Direct Costs Funded: $700,000 <br />Associate Professor <br />Department of Biochemistry <br />School of Medicine <br />Ronald Gregg, Ph.D. <br />Role: Principal Investigator <br />Title: Zebrafish Mutant <br />Mapping Facility <br />Funding Agency: NIH <br />Direct Costs Funded: <br />$237,119 <br />Peer-reviewed <br />Publications: <br />Maddox DM, Vessey KA, <br />Yarbrough GL, Invergo BM, Cantrell DR, Inayat S, Balannik V, Hicks <br />WL, Hawes NL, Byers S, Smith RS, Hurd R, Howell D, Gregg RG, <br />Chang B, Naggert JK, Troy JB, Pinto LH, Nishina PM, McCall MA. <br />Allelic variance between GRM6 mutants, Grm6nob3 and Grm6nob4 <br />results in differences in retinal ganglion cell visual responses. J Physiol. <br />In press (2008). <br />McCall M, Gregg RG. Comparisons of structural and functional <br />abnormalities in mouse b-wave mutants. J Physiol. In press (2008) <br />Marshall CR, Young EJ, Pani AM, Freckmann ML, Lacassie Y, Howald <br />C, Fitzgerald KK, Peippo M, Morris CA, Shane K, Priolo M, Morimoto <br />M, Kondo I, Manguoglu E, Berker-Karauzum S, Edery P, Hobart HH, <br />Mervis CB, Zuffardi O, Reymond A, Kaplan P, Tassabehji M, Gregg <br />RG, Scherer SW, Osborne LR. Infantile spasms is associated with <br />deletion of the MAGI2 gene on chromosome 7q11.23-q21.11. Am J <br />Hum Genet. 83:106-11 (2008). <br />Lee J, Willer JR, Willer GB, Smith K, Gregg RG, Gross JM. Zebrafish <br />blowout provides genetic evidence for Patched1-mediated negative <br />regulation of Hedgehog signaling within the proximal optic vesicle of the <br />vertebrate eye. Dev Biol. 319:10-22 (2008). <br />Gregg RG, Kamermans M, Klooster J, Lukasiewicz PD, Peachey <br />NS, Vessey KA, McCall MA. Nyctalopin expression in retinal bipolar <br />cells restores visual function in a mouse model of complete X-linked <br />congenital stationary night blindness. J Neurophysiol. 98:3023-33 <br />(2007) <br />Palmer CA, Hollis DM, Watts RA, Houck LD, McCall MA, Gregg RG, <br />Feldhoff PW, Feldhoff RC, Arnold SJ. Plethodontid modulating factor, <br />a hypervariable salamander courtship pheromone in the three-finger <br />protein superfamily. FEBS J. 274:2300-10 (2007). <br />21 <br />22 <br />Research Activities: <br />Overview of selected laboratory investigatory areas: <br />• Molecular epidemiology, cancer genetics, etiology and prevention, <br />pharmacogenetics/genomics, personalized medicine, and <br />functional genomics. <br />• Identification of individuals genetically susceptible to the <br />development of cancer from environmental and occupational <br />chemicals in order to focus treatment and prevention strategies <br />on those at greatest risk. <br />• Understanding of the genetic causes for drug failure and/or <br />drug toxicity in order to optimize clinical drug therapy for each <br />individual patient. <br />• The mechanistic and clinical consequences of genetic variation in <br />the biotransformation of carcinogens and drugs. <br />Grants Funded: <br />Role: Program Leader (Cancer Prevention &amp; Control) <br />Title: James Graham Brown P20 Application <br />Funding Agency: NIH/NCI <br />Total Costs Funded: $1,328,613 <br />Role: Principal Investigator <br />Title: Pharmacogenetics of drug and carcinogen metabolism <br />Funding Agency: NIH/NCI <br />Total Costs Funded: $509,635 <br />Role: Principal Investigator <br />Title: Metabolism and toxicity of aromatic <br />amines associated with hair dyes <br />Funding Agency: Procter and Gamble, Inc. <br />Total Costs Funded: $310,885 <br />Role: Principal Investigator <br />Title: Characterization of NAT1 overexpression in breast tumors <br />Funding Agency: NIH/NCI <br />Total Costs Funded: $113,749 <br />Role: Mentor/Co-Investigator <br />Title: Genetic polymorphisms in 5'-UTR of human NAT1 and NAT2 <br />Funding Agency: NIH/NIEHS <br />Total Costs Funded: $145,022 <br />Professor and Chair <br />Department of Pharmacology and <br />Toxicology <br />School of Medicine <br />Role: Principal Investigator <br />Title: Pharmacogenetics of drug and carcinogen metabolism <br />Funding Agency: NIH/NCI <br />Total Costs Funded: $1,724,900 <br />Role: Principal Investigator <br />Title: UofL Environmental Health Sciences Training Program <br />Funding Agency: NIH/NIEHS <br />Total Costs Funded: $697,188 <br />Role: Mentor <br />Title: Cancer Education Grant Program <br />Funding Agency: NIH /NCI <br />Total Costs Funded: $557,437 <br />Role: Center Investigator <br />Title: Center for Environmental Genomics and Integrative Biology <br />Funding Agency: NIH <br />Direct Costs Funded: $4,440,000 <br />Role: Co-Investigator on Project 1 <br />Title: Cardiovascular toxicity of environmental aldehydes <br />Funding Agency: NIH/NIEHS <br />Total Costs Funded: $6,986,060 <br />Role: Principal Investigator <br />Title: NAT1 and NAT2 Genotype Determinations <br />in Cancer Patients and Controls <br />Funding Agency: MD Anderson Cancer <br />Center (pass through of NCI funding) <br />Total Costs Funded: $60,000 <br />Role: Director, Pharmacogenetics Core Laboratory <br />Title: Center for Pediatric Clinical Pharmacology Research <br />Funding Agency: NIH/NICHD <br />Total Costs Funded: $2,248,000 <br />Role: Student Mentor <br />Title: Summer Environmental Health Sciences Training Program <br />Funding Agency: NIEHS <br />Total Costs Funded: $158,355 <br />David W. Hein, Ph.D. <br />Role: Sub-project Principal Investigator <br />Title: Nashville Breast Health Study <br />Funding Agency: Vanderbilt University (pass through of NCI funding) <br />Total Costs Funded: $134,006 <br />Role: Co-investigator <br />Title: A pharmacogenetic approach to prostate cancer susceptibility <br />Funding Agency: NCI <br />Total Costs Funded: $148,000 <br />Role: Investigator/Mentor <br />Title: Planning Grant for Louisville Clinical <br />and Translational Science Award <br />Funding Agency: NIH <br />Total Costs Funded: $220,000 <br />Role: Principal Investigator <br />Title: NAT1 and NAT2 Metabolism Studies with Hair Dye Arylamines <br />Funding Agency: Procter and Gamble, Inc. <br />Total Costs Funded: $100,000 <br />Role: Co-Investigator <br />Title: Polymorphic genes of detoxification <br />enzymes as risk factors for PSP <br />Funding Agency: UofL Center for Environmental <br />Genomics and Integrative Biology <br />Total Costs Funded: $30,000 <br />23 <br />Role: Mentor <br />Title: N-acetyltransferase 1 polymorphism and breast cancer risk <br />Funding Agency: Department of Defense <br />Breast Cancer Research Program <br />Total Costs Funded: $92,442 <br />Peer-reviewed Publications: <br />Zang, Y., Zhao, S., Doll, M.A., States, J.C. and Hein, D.W.: Functional <br />characterization of the A411T (L137F) and G364A (D122N) genetic <br />polymorphisms in human N-acetyltransferase 2. Pharmacogenetics <br />and Genomics 17: 37-45, 2007. <br />Husain, A., Zhang, X., Doll, M.A., States, J.C., Barker, D.F. and Hein, <br />D.W.: Identification of N-acetyltransferase 2 (NAT2) transcription start <br />sites and quantitation of NAT2-specific mRNA in human tissues. Drug <br />Metabolism and Disposition 35: 721-727, 2007. (Epub February 7). <br />Metry, K.J., Zhao, S., Neale, J.R., Doll, M.A., States, J.C., McGregor, <br />W.G., Pierce Jr., W.M., and Hein, D.W.: 2-amino-1-methyl-6- <br />phenylimidazo [4,5-b]pyridine (PhIP)-induced DNA adducts and <br />genotoxicity in chinese hamster ovary (CHO) cells expressing human <br />CYP1A2 and rapid or slow acetylator N-acetyltransferase 2. Molecular <br />Carcinogenesis 46: 553-563, 2007. (Epub February 12). <br />Walraven, J.M., Trent, J.O. and Hein, D.W.: Computational and <br />experimental analyses of mammalian arylamine N-acetyltransferase <br />structure and function. Drug Metabolism and Disposition 35: 1001- <br />1007, 2007. (Epub March 19). <br />Zang, Y., Doll, M.A., Zhao, S., States, J.C. and Hein, D.W.: Functional <br />characterization of single nucleotide polymorphisms and haplotypes of <br />human N-acetyltransferase 2. Carcinogenesis 28: 1665-1671, 2007. <br />(Epub April 13). <br />Rothman, N., Garcia-Closas, M., and Hein, D.W.: Commentary: <br />Reflections on G.M. Lower and colleagues’ 1979 study associating <br />slow acetylator phenotype with urinary bladder cancer: metaanalysis, <br />historical refinements of the hypothesis, and lessons learned. <br />International Journal of Epidemiology 36: 23-28, 2007. <br />Lubin, J.H., Kogevinas, M., Silverman, D., Malats, N., Garcia-Closas, <br />M., Tardon, A., Hein, D.W., Garcia-Closas, R., Serra, C., Dosemeci, <br />M., Carrato, A., and Rothman, N.: Evidence for an intensitydependent <br />interaction of NAT2 acetylation genotype and cigarette <br />smoking in the Spanish Bladder Cancer Study. International Journal of <br />Epidemiology 36: 236-241, 2007. <br />24 <br />Morton, L.M., Bernstein, L., Wang, S.S., <br />Hein, D.W., Rothman, N, Colt, J.S., Davis, <br />S., Cerhan, J.R., Severson, R.K., Welch, <br />R., Hartge, P., and Zahm, S.H.: Hair dye use, <br />genetic variation in N-acetyltransferase 1 (NAT1) <br />and 2 (NAT2), and risk of non-Hodgkin lymphoma. <br />Carcinogenesis 28: 1759-1764, 2007. (Epub May <br />23). <br />Mahid, S.S., Colliver, D.W., Crawford, N.P., <br />Martini, B.D., Doll, M.A., Hein, D.W., Cobbs, G.A., <br />Petras, R.E. and Galandiuk, S.: Characterization of <br />N-acetyltransferase 1 and 2 polymorphisms and haplotype <br />analysis for inflammatory bowel disease and sporadic colorectal <br />carcinoma. BMC Medical Genetics 8: 28, 2007. (Epub May 30). <br />Walraven, J.M., Barker, D.F., Doll, M.A. and Hein, D.W.: Tissue <br />expression and genomic sequences of rat N-acetyltransferases rNat1, <br />rNat2, rNat3, and functional characterization of a novel rNat3*2 genetic <br />variant. Toxicological Sciences 99: 413-421, 2007. (Epub June 12) <br />Husain, A., Zhang, X., Doll, M.A., States, J.C., Barker, D.F. and Hein, <br />D.W.: Functional analysis of the human N-acetyltransferase 1 major <br />promoter: Quantitation of tissue expression and identification of critical <br />sequence elements. Drug Metabolism and Disposition 35: 1649-1656, <br />2007. (Epub June 25). <br />Bendaly, J., Zhao, S., Neale, J.R., Metry, K.J., Doll, M.A., States, J.C., <br />Pierce Jr., W.M. and Hein, D.W.: 2-Amino-3,8-dimethylimidazo-[4,5-f] <br />quinoxaline-induced DNA adduct formation and mutagenesis in DNA <br />repair deficient CHO cells expressing human CYP1A1 and rapid or slow <br />acetylator N-acetyltransferase 2. Cancer Epidemiology, Biomarkers &amp; <br />Prevention 16: 1503-1509, 2007. <br />Husain, A., Loehle, J.A. and Hein, D.W.: Clinical pharmacogenetics in <br />pediatric patients. Pharmacogenomics 8: 1403-1411, 2007. <br />Jiao, L., Doll, M.A., Hein, D.W., Bondy, M.L., Hassan, M.M., Hixson, <br />J.E., Abbruzzese, J.L., and Li, D.: Haplotype of N-acetyltransferase 1 <br />and 2 and risk of pancreatic cancer. Cancer Epidemiology, Biomarkers <br />&amp; Prevention 16: 2379-2386, 2007. <br />Ravoori, S., Feng, Y., Neale, J.R., Jeyabalan, J., Srinivasan, C., <br />Hein, D.W. and Gupta, R.C.: Dose-dependent reduction of <br />3,2’-dimethyl-4-aminobiphenyl-derived DNA adducts in colon <br />and liver of rats administered celecoxib. Mutation Research <br />638: 103-109, 2008. (Epub September 14, 2007). <br />Wakefield, L., Cornish, V., Long, H., Kawamura, <br />A., Zhang, X., Hein, D.W., and Sim, E.: Mouse <br />arylamine N-acetyltransferase 2 (Nat2) expression <br />during embryogenesis; a potential marker for the <br />developing neuroendocrine system. Biomarkers 13: <br />106-118, 2008. (Epub September 25, 2007). <br />Zhu, Y. and Hein, D.W.: Functional effects of single <br />nucleotide polymorphisms in the coding region of human <br />N-acetyltransferase 1. The Pharmacogenomics Journal 8: 339-348, <br />2008. (Epub October 2, 2007). <br />Feng, Y., Neale, J.R., Doll, M.A. and Hein, D.W.: Chemoprevention <br />of arylamine-induced colorectal aberrant crypts. Experimental Biology <br />and Medicine 233: 71-75, 2008. <br />Walraven, J.M., Trent, J.O. and Hein, D.W.: Structurefunction <br />analyses of single nucleotide polymorphisms in human <br />N-acetyltransferase 1. Drug Metabolism Reviews 40: 169-184, 2008. <br />Shin, A., Shrubsole, M.J., Rice, J.M., Cai, Q., Doll, M.A., Long, J., <br />Smalley, W.E., Shyr, Y., Sinha, R., Ness, R.M., Hein, D.W. and Zheng, <br />W.: Meat intake, heterocyclic amine exposure, and metabolizing <br />enzyme polymorphisms in relation to colorectal polyp risk. Cancer <br />Epidemiology, Biomarkers &amp; Prevention 17: 320-329, 2008. <br />Hein, D.W., Boukouvala, S., Grant, D.M., Minchin, R.F. and Sim, <br />E.: Changes in consensus arylamine N-acetyltransferase (NAT) gene <br />nomenclature. Pharmacogenetics and Genomics 18: 367-368, 2008. <br />Martin, R.C.G., Barker, D.F., Doll, M.A., Pine, S., Mechanic L., <br />Bowman, E.D., Harris, C.C. and Hein, D.W.: Manganese superoxide <br />dismutase gene coding region polymorphisms lack clinical incidence in <br />general population. DNA and Cell Biology 27: 321-323, 2008. (Epub <br />May 8). <br />David W. Hein, Ph.D., continued <br />25 <br />Suzuki, H., Morris, J.S., Li Y., Doll, M.A., Hein, D.W., Liu, J., Jiao, <br />L., Hassan, M.M., Day, R.S., Bondy, M.L., Abbruzzese, J.L., and <br />Li, D.: Interaction of the cytochrome P4501A2, SULT1A1, and NAT <br />gene polymorphisms with smoking and dietary mutagen intake in <br />modification of the risk of pancreatic cancer. Carcinogenesis 29: 1184- <br />1191, 2008. (Epub May 21). <br />Walraven, J.M., Zang, Y., Trent, J.O. and Hein, D.W.: Structure/ <br />function evaluations of single nucleotide polymorphisms in human <br />N-acetyltransferase 2. Current Drug Metabolism 9: 471-486, 2008. <br />Zhou, G., Li, X., Hein, D.W., Xiang, X., Marshall, J.P., Prabhu, S.D. and <br />Cai, L.: Metallothionein suppresses angiotensin II-induced nicotinamide <br />adenine dinucleotide phosphate oxidase activation, nitrosative stress, <br />apoptosis, and pathological remodeling in the diabetic heart. Journal <br />of the American College of Cardiology 52: 655-666, 2008. <br />Neale, J.R., Smith, N.B., Pierce Jr., W. M., and Hein, D.W.: Methods <br />for aromatic and heterocyclic amine carcinogen-DNA adduct analysis <br />by liquid chromatography-tandem mass spectrometry. Polycyclic <br />Aromatic Compounds 28: 402-417, 2008.. <br />Morton, L.M., Wang, S.S., Cozen, W., Linet, M.S., Chatterjee, N., <br />Davis, S., Severson, R.K., Colt, J.S., Vasef, M.A., Rothman, N., Blair, <br />A., Bernstein, L., Cross, A.J., De Roos, A. J., Engels, E.A., Hein, D.W., <br />Hill, D.A., Kelemen, L.E., Lim, U., Lynch, C.F., Schenk, M., Wacholder, <br />S., Ward, M.H., Zahm, S.H., Chanock, S.J., Cerhan, J.R., and Hartge, <br />P.: Etiologic heterogeneity among non-Hodgkin lymphoma subtypes. <br />Blood (Epub September 16, 2008). <br />Hein, D.W., Bendaly, J., Neale, J.R., and Doll, M.A.: Systemic <br />functional expression of N-acetyltransferase polymorphism in the F344 <br />Nat2 congenic rat. Drug Metabolism and Disposition 36: 2452-2459, <br />2008 (Epub September 17). <br />Barker, D.F., Walraven, J.M., Ristagno, E.H., Doll, M.A. and Hein, D.W.: <br />Quantitative tissue and gene specific differences and developmental <br />changes in Nat1, Nat2 and Nat3 mRNA in the rat. Drug Metabolism <br />and Disposition 36: 2445-2451, 2008. (Epub September 17, 2008). <br />Kennedy, M.J., Loehle, J.A., Griffin, A.R., Doll, M.A., Kearns, <br />G.L., Sullivan, J.E. and Hein, D.W.: Association of the histamine <br />N-methyltransferase C314T (Thr105Ile) polymorphism with atopic <br />dermatitis in Caucasian children. Pharmacotherapy28: 1495-1501, <br />2008. <br />Martin, R.C.G., Li, Y., Liu, Q., Jensen, N.S., Barker, D.F., Doll, M.A. and <br />Hein, D.W.: Manganese superoxide dismutase V16A single nucleotide <br />polymorphism in the mitochondrial targeting sequence is associated <br />with reduced enzymatic activity in cryopreserved human hepatocytes. <br />DNA and Cell Biology (Epub September 26, 2008). <br />Jefferson, F.A., Xiao, G. H., and Hein, D.W.: 4-Aminobiphenyl <br />down regulation of NAT2 acetylator genotype-dependent N- and <br />O-acetylation of aromatic and heterocyclic amine carcinogens in <br />primary mammary epithelial cell cultures from rapid and slow acetylator <br />rats. Toxicological Sciences (Epub October 8, 2008). <br />Goebel, C., Hewitt, N.J., Kunze, G., Wenker, M., Hein, D.W, Beck, H., <br />Skare, J.: Skin metabolism of aminophenols: Human keratinocytes <br />as a suitable in vitro model to qualitatively predict the dermal <br />transformation of 4-amino-2-hydroxytoluene in vivo. Toxicology and <br />Applied Pharmacology (Epub November 28, 2008). <br />Research Activities: <br />An important goal in birth defects research is to derive the architecture <br />and function of developing systems as biological networks. At the Birth <br />Defects Center, Dr. Knudsen’s laboratory used genomic and systems <br />biology to understand the developmental consequences of prenatal <br />exposures to alcohol and environmental toxicants. With vast genomics <br />data and bioinformatics tools now at hand, efforts are underway to <br />reverse-engineer gene regulatory networks (GRNs) that underlie birth <br />defects and developmental abnormalities. Dr. Knudsen’s research <br />focuses on ‘virtual tissues’ whereby computational embryology and <br />developmental computational techniques are being implemented to <br />understand toxicity processes in complex biological systems. A longterm <br />goal of this new research is to develop a sophisticated computer <br />model of a mammalian embryo that can be used to help scientists <br />better understand the prenatal risks posed by chemicals and other <br />environmental stressors. This project is using computers to develop <br />models of GRNs and reconstruct embryonic tissues in silico (http:// <br />www.epa.gov/ncct/v-Embryo/). ‘Virtual tissue’ technology enables <br />researchers to interact with a computer-simulated environment of <br />specific embryonic tissues. The ability to perform complex operations <br />on simulated system gives insight to conditions hard to evaluate due to <br />time, scale, and cost (monetary and animal). Challenges for technology <br />development include a knowledgebase to extract, organize, and store <br />data (database) and facts (literature) about the tissue in a computable <br />form, and a simulation engine for multi-scale models to study how <br />different mechanisms interact at one level and cause effects at a <br />higher level. Validated computational (in silico) models of the embryo <br />may someday help scientists integrate in vitro data at different scales <br />molecules to phenotype as well as to help link toxicity pathways with <br />prenatal developmental effects in vivo. <br />26 <br />Adjunct Professor <br />Department of Molecular, Cellular &amp; <br />Craniofacial Biology <br />School of Dentistry <br />Developmental Systems Biologist <br />Thomas B. Knudsen, Ph.D. <br />Professor and Director <br />Division of Maternal-Fetal Medicine <br />Department of Obstetrics, Gynecology <br />&amp; Women’s Health <br />School of Medicine <br />Jeffrey C. King, M.D. <br />Research Activities: <br />The Division of Maternal-Fetal Medicine <br />includes 5 sub-specialty trained <br />obstetricians along with their support <br />staff of sonographers, medical assistants, <br />counselors, and others that provide both consultative and <br />direct patient care for women with a wide variety of medical or surgical <br />complications of pregnancy. Some of the conditions that might <br />qualify a women to see a Maternal-Fetal Specialist include a prior <br />history of preterm delivery, multifetal pregnancy (triplets or greater), <br />pre-pregnancy diabetes (Type I or II), chronic hypertension, severe <br />asthma, or advanced maternal age. Additionally, complications <br />that develop during the pregnancy such as inadequate fetal growth, <br />suspected fetal anomaly, premature rupture of the membranes, preterm <br />labor, antepartum hemorrhage, and preeclampsia often necessitate <br />consultation with a Maternal-Fetal Specialist. <br />Additionally, we provide teaching and oversight for the University <br />of Louisville medical students and the Obstetric and Gynecologic <br />residents-in-training. <br />One of our primary fetal assessment tools is ultrasound imaging <br />of the fetus. Using ultrasound we are able to visualize (if the fetus <br />cooperates) and evaluate the <br />major structures within the <br />fetus. We are able to assess <br />the fetus for major structural <br />abnormalities and counsel <br />them regrading prognosis. <br />Our research interests <br />are varied and include <br />vaccination protection, identification of patients at risk for preterm labor, <br />hypertension management, prenatal diagnosis, patient safety initiatives, <br />and various maternal outcomes. <br />Peer-reviewed Publications: <br />Lang CT, King JC. Maternal mortality in the United States. Best Pract <br />Res Clin Obstet Gynaecol. 2008 Jun; 22(3): 517-31. <br />Lang CT, King JC. The burden of maternal mortality and morbidity in <br />the United States and worldwide. In Handbook of Diseases Burden <br />and Quality of Life Measures, Prof Preedy (ed) Springer-Verlag, Berlin, <br />Chapter 310, 2008. <br />Grants Funded: <br />Role: Co-Principal Investigator with Dr. Michele Pisano <br />Title: Response Signatures of Alcohol Related Birth Defects <br />Funding Agency: NIH <br />Direct Costs Funded: $221,582 <br />Role: Co-Principal Investigator with Dr. Michele Pisano <br />Title: Perinatal Breast Cancer Programming: fat and estrogens <br />Funding Agency: NIH <br />Direct Costs Funded: $104,000 <br />Role: Co-Investigator; PI Ken Ramos <br />Title: Center for Environmental Genomics and Integrative Biology <br />Funding Agency: NIH <br />Role: Co-Investigator; PI Denis Knane <br />Title: Epithelial cell TLRs in disease susceptibility <br />Funding Agency: NIH <br />Peer-reviewed Publications: <br />Green ML, Singh AV, Zhang Y, Nemeth KA, Sulik KK and Knudsen TB. <br />Reprogramming of genetic networks during initiation of the fetal alcohol <br />syndrome. Devel Dynam 236: 613-631 (2007). <br />Singh AV, Knudsen KB and Knudsen TB. Integrative Analysis of the <br />mouse embryonic transcriptome. Bioinformation 1: 24-30 (2007). <br />Singh AV, Rouhka EC, Rempala GA, Bastian CD and Knudsen TB. <br />Integrative database management for mouse development: systems <br />and concepts. Birth Defects Res C (2007) 81: 1-19. <br />Calabrese EJ, et al., Knudsen TB, et al. Biological Stress Response <br />Terminology: Integrating the concepts of adaptive response and <br />preconditioning stress within a hormetic dose-response framework. <br />Toxicol Appl Pharmacol 222:122-128 (2007). <br />Deaciuc IV, Song Z, Peng X, Barve SS, Song M, He Q, Knudsen TB, <br />Singh AV, and McClain CJ. Genome-wide transcriptome expression <br />in the liver of a mouse model of high carbohydrate diet-induced liver <br />steatosis and its significance for the disease. Hepatol International <br />2:39-49 (2008). <br />Barthold JS, McCahan, Singh AV, Knudsen TB, Si X, Campion L and <br />Akins RE. Altered expression of muscle and cytoskeleton-related genes <br />in a rat strain with inherited cryptorchidism. J Androl. 29:352-366 <br />(2008). <br />Datta S, Turner D, Singh R, Ruest LB, Pierce WM Jr and Knudsen <br />TB. Fetal Alcohol Syndrome (FAS) in C57BL/6 mice detected through <br />proteomics screening of the amniotic fluid. Birth Defects Res A 82:177- <br />186 (2008). <br />Knudsen TB and Kavlock RJ. Comparative bioinformatics and <br />computational toxicology. In: Developmental Toxicology 3rd edition. (B <br />Abbott and D Hansen, editors) New York: Taylor and Francis, Chapter <br />12 pp 311-360 (2008) <br />27 <br /> <br />Zhang H, Denhard LD, Zhou H, Liu L, Lan ZJ. 0610009K11Rik, a <br />testis-specific and germ cell nuclear receptor-interacting protein. <br />Biochem Biophysic Res Commun 366(4):898-904 (2008). <br />Reddy P, Liu L, Adhikari D, Jagarlamudi K, Rajareddy S, Shen Y, Du <br />C, Tang W, Hämäläinen T, Peng SL, Lan ZJ, Cooney AJ, Huhtaniemi <br />I, and Liu K. Oocyte-specific deletion of Pten causes activation of the <br />entire pool of primordial follicles. Science 319(5863):611-613 (2008). <br />Li Z, Zhang H, Denhard LA, Liu LH, Zhou H, Lan ZJ. Reduced white <br />fat mass in adult mice bearing a truncated Patched 1. Int J Biol Sci <br />4(1):29-36 (2008). <br />Lan ZJ, Zhang H, Zhou H, Liu J, Denhard LA, Cooney AJ. (2008) <br />Oocyte-specific expression of fibroblast growth factor 8 and its role in <br />ovarian development. 41st Annual Meeting of the Society for the Study <br />of Reproduction, Kona, HW, May 27-30, 2008. <br />28 <br />Research Activities: <br />Our laboratory is mainly interested in understanding the functional <br />roles of germ cell-expressing genes in male and female reproduction. <br />Currently we are investigating the roles of fibroblast growth factors, <br />ring/zinc finger proteins and hedgehog signaling molecules in those <br />processes. We combine mouse genetic, molecular and cellular <br />approaches to address the roles of these genes during reproduction. <br />Characterization of the functions of these genes in the gonads would <br />provide new leads for development of contraceptive agents, and <br />diagnostic reagents and therapeutic medicines for infertility. In addition, <br />we are also interested in exploring the role of ring/zinc finger proteins in <br />steroid nuclear receptor action in the ovary and mammary gland in vivo <br />and in vitro. The potential roles of human orthologs for ring/zinc finger <br />proteins in breast and ovarian cancers are also being investigated. <br />Grants Funded: <br />Role: COBRE supported junior investigator <br />Title: The role of germ-cell expressing genes in reproduction <br />Funding Agency: National Institutes of Health/ <br />National Center for Research Resources <br />Direct Costs Funded: $157,500 <br />Peer-reviewed Publications: <br />Zhao H, Li Z, Cooney AJ, Lan ZJ. Orphan nuclear receptor function in <br />the ovary. Frontier in Bioscience 12:3398-3405 (2007). <br />Assistant Professor <br />Department of Molecular, Cellular and <br />Craniofacial Biology <br />School of Dentistry <br />Zi-Jian Lan, Ph.D. <br />Research Activities: <br />My researches aim to investigate the function roles of three crosslyrelated <br />receptor tyrosine kinases, Tyro3, Axl, MerTK (TAM), particularly <br />the functions of the MerTK in regulation of the retinal pigmental <br />epithelial (RPE) cell for phagocytic clearance of the spent photoreceptor <br />out segments. MerTK null mutation causes human retinitis pigmentosa <br />(RP), a group of inherited retinal degenerative diseases with a <br />worldwide prevalence of 1:3500, and eventually leads to complete <br />blindness. Our goal aims to elucidate the molecular mechanism of <br />the MerTK regulation on RPE phagocytosis through studies of the <br />MerTK regulated candidate genes that may in turn affect RPE function <br />or through investigations of the MerTK-mediated signal transduction <br />pathways that subsequently regulate cytoskeletonal rearrangement <br />during process of the phagocytosis. With progresses of our studies, <br />we expect to gain new knowledge and understanding of the RPE <br />function, which will allow us to develop and implement new therapies <br />for treatment of RP caused by RPE dysfunction. <br />Grants Funded: <br />Role: Principal Investigator <br />Title: MerTK regulation of the PTTG and RPE phagocytosis <br />Funding Agency: NIH/NEI <br />Direct Costs Funded: $1,250,000 <br />Peer-reviewed Publications: <br />Wang H, Chen S, Chen Y, Wang H, Wu H, Tang H, Xiong W, Ma J, Ge <br />Y, Lu Q, Han D. The role of Tyro 3 subfamily receptors in the regulation <br />of hemostasis and megakaryocytopoiesis. Haematologica. 92:643-650 <br />(2007). <br />Xiong W, Chen Y, Wang H, Wu H, Lu Q, Han D. Gas6 and the Tyro 3 <br />receptor tyrosine kinase subfamily regulate the phagocytic function of <br />Sertoli cells. Reproduction 135:77-87 (2008). <br />Assistant Professor <br />Department of Ophthalmology and <br />Visual Sciences <br />School of Medicine <br />Qingxian Lu <br />Research Activities: <br />Scholarship this past year was focused on the development of Near <br />Infrared Spectroscopy (NIRS) as an assessment tool in the Neonatal <br />Intensive Care Unit as well as the presentation of findings from some <br />pilot work achieved while working under the P20 from the Birth Defects <br />Center. I am now participating in a neonatal registry for infants that <br />is using NIRS technology. The focus of my research trajectory is on <br />novel approaches to care in the NICU; the paper on Bubble CPAP <br />with a graduate student fell under this domain. A new schemata for <br />categorizing interventions in the NICU was developed using a Delphi <br />Technique at the national level and was published and presented. This <br />schemata will be useful during observations in the NICU of procedures <br />performed by nurses and physicians, and will aid in the analysis of ROM <br />data. Pilot data from a previous R15 was published that will direct <br />future funding efforts. Currently I am collaborating with a Psychiatrist, <br />a Neonatologist, a Chemist, a Chemical Engineer, a Statistician, a <br />Social Psychologist, and two PhD Communication faculty on several <br />interprofessional teams. These collaborations are evidenced in my <br />publication record. One commentary on published research in my field <br />was solicited and published. I just completed a 3 year term as the Chair <br />of the Research Committee of my professional association and currently <br />serve as the Research Section Editor for the affiliated journal. <br />As the Associate Dean for Graduate Academic Affairs in the School <br />of Nursing, I direct 5 Master of Science in Nursing Program Tracks as <br />well as a PhD in Nursing. We are also in the process of developing <br />a practice doctorate that will be submitted for review to the School <br />for Interdisciplinary and Graduate Studies this academic year. Active <br />in university affairs, I serve on the university and the HSC technology <br />Associate Professor and Associate Dean <br />for Graduate Academic Affairs <br />School of Nursing <br />29 <br />Rosalie Mainous, Ph.D.* <br />Research Activities: <br />Dr. Dennis L. Molfese is an internationally recognized expert on the use <br />of brain electrical recording techniques to study the emerging relationship <br />between brain development and cognitive processes. He has six active <br />NIH, NASA and DOE research grants that fund research into the early <br />identification and treatment of babies and young children at risk for <br />developing reading and math disabilities, the precursors of dyslexia with <br />Dr. Victoria Molfese at the University of Louisville, the long-term impact <br />of prenatal exposure to cocaine on child cognitive development with Dr. <br />Linda Mayes at the Yale University Child Study Center, an investigation <br />into the brain correlates of successful language interventions with <br />children who have selective language impairments with Dr. Paul Yoder of <br />the Kennedy Center at Vanderbilt University, and a study of the impact <br />of mild sleep reductions on children’s neural processing with Dr. David <br />Gozal in the Department of Pediatrics at the University of Louisville. <br />NASA funds his research into changes in brain processing that occur <br />during extended space travel. <br />Dr. Molfese received his Ph.D. in Psychology from the Pennsylvania State <br />University in 1972. He is currently a Distinguished University Scholar <br />and Professor in the Birth Defects Center at the University of Louisville. <br />Dr. Molfese served as a member and Chair of numerous of NIH grant <br />review panels on Learning Disabilities. He is co-director of one of 15 <br />national laboratories that make up the <br />National Institutes of Health Reading <br />and Learning Disabilities Research <br />Network. He is a Fellow of the <br />American Psychological Association <br />and the American Psychological <br />Society and serves as Editor-in- <br />Chief for the scientific journal, <br />Developmental Neuropsychology. <br />He was recently recognized as <br />“Psychologist of the Year” (2007) by <br />the Kentucky Psychological Association. In addition to his collaborations <br />and consultations with a number of laboratories in the USA, Finland, and <br />The Netherlands, Dr. Molfese also serves as a consultant on infant and <br />child development issues to the country of Belize, C.A. <br />Grants Funded: <br />Role: Principal Investigator <br />Title: Impact of Sleep, Microgravity and <br />Stress on Cognition &amp; the Brain <br />Funding Agency: NASA <br />Direct Costs Funded: $1,839,383 <br />30 <br />Dennis L. Molfese, Ph.D. <br />committees and am the point person in the SON ROM on technology. <br />As a Neonatal Nurse Practitioner, I am active at the national level in <br />several venues as the director of the NNP program and participate in <br />the development of educational standards for NNPs. I am developing a <br />mechanism for the evaluation of online teaching and advocate for new <br />technology in the teaching arena including the use of Tegrity, wikis, blogs, <br />and videoconferencing in real time. I currently teach Genetics, Evidence <br />Based Practice, and Neonatal Pathophysiology at the master’s level ROM <br />and direct doctoral students in Leadership and Research Practicums. <br />Grants Funded: <br />Role: Principal Investigator <br />Title: Nursing Workforce Development Grant <br />Funding Agency: US Department of Health and Human Services <br />Direct Costs Funded: $36,538 <br />Peer-reviewed Publications: <br />Bonner, K &amp; Mainous, R. O. The nursing care of the infant receiving <br />bubble CPAP therapy. Advances in Neonatal Care 8: 78-95 (2008). <br />Mainous, R. O. &amp; Looney, S. A pilot study of changes in cerebral blood <br />flow velocity, resistance and vital signs following a painful stimulus in the <br />premature infant. Advances in Neonatal Care 7: 88-104 (2007). <br />Mainous, R. O. Commentary on Venipuncture Verses Heel Lance <br />for Blood Sampling in Term Neonates, (Systematic review), Evidence- <br />Based Nursing 11: 72 (2008). <br />Martin, C. A., Mainous, A. G. III, Ford, H. H., Mainous, R.O., Slade, S., Martin, <br />D., &amp; Omar, H. A., Alcohol, impulsive behavior and guns. In Adolescence and <br />Alcohol, Tel Aviv: Freund Publishing House, p. 25-31 (2007). <br />Mainous, R.O. A delphi study on categorization of noxious stimuli in <br />the NICU, Advances in Neonatal Care 8: 135 (2007). <br />* Dr. Mainous’ full title is: Dr. Rosalie Mainous, Ph.D., ARNP, NNP-BC <br />Professor <br />Department of Molecular, Cellular &amp; <br />Craniofacial Biology <br />Distinguished University Scholar <br />School of Dentistry <br />Role: Principal Investigator <br />Title: Space Flight and Exploration: The impact on perception, <br />cognition, sleep, and brain physiology <br />Funding Agency: NASA <br />Direct Costs Funded: $1,984,000 <br />Role: Principal Investigator <br />Title: Sleep and Psychophysiological Function in Children <br />Funding Agency: NIH: National Heart, Lung, and Blood Institute <br />Direct Costs Funded: $1,837,500 <br />Role: Co-Investigator <br />Title: ERP and Behavioral predictors of language intervention <br />Funding Agency: NIDCD <br />Direct Costs Funded: $2,340,268 <br />Role: Co-Investigator <br />Title: Scaling Up the Implementation of a Pre-Kindergarten <br />Mathematics Curriculum in Public Preshool Programs <br />Funding Agency: U.S. Department of Education <br />Direct Costs Funded: $2,000,000 <br />Role: Principal Investigator <br />Title: Neonatal Dyslexia Screening Device for Clinical Use <br />Funding Agency: NICHD <br />Direct Costs Funded: $126,000 <br />Role: Co-Investigator <br />Title: Cocaine-Exposed Children &amp; ERP Studies of Neurocognition <br />Funding Agency: NIH/NIDA <br />Direct Costs Funded: $1,850,000 <br />Role: Co-Investigator <br />Title: Scaling Up the Implementation of a Pre-Kindergarten <br />Mathematics Curriculum in Public Preschool Programs <br />Funding Agency: U.S. Department of Education <br />Direct Costs Funded: $2,000,000 <br />Peer-reviewed Publications: <br />Molfese, D. L., Molfese, V. J., &amp; Pratt, N. L. (2007). The Use Of Event- <br />Related Evoked Potentials To Predict Developmental Outcomes. In M. <br />de Haan (Ed.), Infant EEG and Event-Related Potentials. Psychology <br />Press: Hove, UK. <br />Molfese, D., Molfese, V. &amp; Molfese, P. (2007). Relation Between Early <br />Measures Of Brain Responses To Language Stimuli and Childhood <br />Performance On Behavioral Language Tasks. In D. Coch, G. Dawson, <br />&amp; K. Fischer (Eds). Human Behavior and the Developing Brain, Second <br />Edition: Atypical Development (pp 191-211). New York: Guilford <br />Publications, Inc. <br />Key, A., Ferguson, M., Molfese, D., Peach, K., Lehman, C. &amp; Molfese <br />V. (2007). Smoking during pregnancy affects speech discrimination <br />ability in newborn infants. Environmental Health Perspectives, 115(4), <br />623-629. <br />Molfese, V., Molfese, D., Beswick, J., Jacobi-Vessels, J., Molfese, P., <br />Molnar, A., Wagner, M., Haines, B. (2008). Event Related Potentials To <br />Identify Language and Reading Skills. Topics in Language Disorders, <br />28, 28-45. <br />31 <br />Research Activities: <br />Victoria J. Molfese is the Ashland/Nystrand Chair in Early Childhood <br />Education and Professor in the Department of Teaching and Learning <br />at the University of Louisville. She is also the Director of the Center <br />for Research in Early Childhood. She has published journal articles, <br />books, and book chapters in the area of cognitive development in <br />infants, children and adults. She has received grants in support of <br />research activities, including an NIH funded longitudinal research grant <br />on electrophysiological and behavioral predictors of language and <br />cognitive development in children from birth through age 13 years. <br />Additional grant funding was received to study the development of <br />reading and mathematical skills in preschool children, the development <br />of personality in twin infants and their parents, and to study the impacts <br />of sleep disturbances on the behaviors of children as well as adults. <br />Her work has been funded by grants from National Institutes of Health, <br />March of Dimes, U.S. Department of Education, U.S. Department <br />of Health and Human Services, the Kellogg Foundation, and NASA. <br />Research is currently underway on early predictors of reading and <br />mathematic abilities in both infants and preschool children, home and <br />school characteristics that influence learning in early childhood, the <br />development of interventions for infants and preschool children to <br />mitigate the development of learning disabilities, and an investigation <br />of the influence of school-based and home-based intervention on the <br />development of mathematical and early literacy skills of preschool <br />children at risk due to poverty. <br />Grants Funded: <br />Role: Co-Investigator <br />Title: Scaling Up the Implementation of a Pre-Kindergarten <br />Mathematics Curriculum in Public Preschool Programs <br />Funding Agency: U.S. Department of Education <br />Direct Costs Funded: $2,000,000 <br />Role: Co-Investigator <br />Title: Impact of Sleep, Microgravity and <br />Stress on Cognition and the Brain <br />Funding Agency: NASA <br />Direct Costs Funded: $1,980,000 <br />Role: Co-Investigator <br />Title: The Impact Of The Microgravity Environment On Perception, <br />Cognition, Sleep, and Brain Physiology <br />Funding Agency: NASA <br />Direct Costs Funded: $1,980,000 <br />Ashland/Nystrand Chair in Early <br />Childhood Education <br />Associate Editor <br />Developmental Neuropsychology <br />Center for Research in Early Childhood <br />College of Education and Human <br />Development <br />32 <br />Victoria J. Molfese Ph.D. <br />Kook, H., Gupta, L., Kota, S., Molfese, D.L., &amp; Lyytinen, H. (2008), <br />“An Offline/Real-Time Artifact Rejection Strategy to Improve the <br />Classification of Multi-Channel Evoked Potentials, Pattern Recognition, <br />41, 1985-1996. <br />Molfese, D., Molfese, V., Barnes, M., Warren, C., &amp; Molfese, P. (2008). <br />Familial predictors of dyslexia: Evidence from preschool children with <br />and without familial dyslexia risk. In V. Berninger, A. Fawcett, G. Reid <br />&amp; L Siegel (Eds). Handbook of Dyslexia. New York Sage Publications, <br />99-120. <br />Tan, A. &amp; Molfese, D. L. (2009). ERP Correlates of Noun and Verb <br />Processing in Preschool-Age Children. Biological Psychology, 80 (1), (In <br />press). <br />Molfese, D., Molfese, V., &amp; Beswick, J., Jacobi-Vessels, J., Molfese, <br />P. &amp; Starkey, G. (2008). Dynamic Links Between Emerging Cognitive <br />Skills and Brain Processes. Special Issue on Neurobiological <br />and experiential dimensions of dyslexia: Multiple perspectives. <br />Developmental Neuropsychology, 33(6), 682–706. <br />Role: Investigator <br />Title: Sleep and Sleep Disorders in Children <br />Funding Agency: National Institutes of Health <br />Direct Costs Funded: $1,800,000 <br />Peer-reviewed Publications: <br />Jung, E., Molfese, V., Beswick, J., Jacobi-Vessels, J., &amp; Molnar, <br />A. (in press). Growth of Cognitive Skills in Preschoolers: Impacts of <br />Sleep Habits and Learning-Related Behaviors. Early Education and <br />Development. <br />Molfese, D., Molfese, V., &amp; Beswick, J., Jacobi-Vessels, J., &amp; Molfese, <br />P. (in review). Dynamic Links Between Emerging Cognitive Skills and <br />Brain Processes. Special Issue on Neurobiological and experiential <br />dimensions of dyslexia: Multiple perspectives. Developmental <br />Neuropsychology. <br />Jung, E., Larson, A. E., Molfese, V. J., &amp; Thompson, C. (2008). <br />Research-based teacher candidate dispositions assessment system: <br />Moving forward. Journal of Education for Teaching, 34, 155-156. <br />Brown, E. T., Molfese, V. &amp; Molfese, P. (2008). Preschool Student <br />Learning in Literacy and Mathematics: Impact of Teacher Experience, <br />Qualifications, and Beliefs On An At-Risk Sample. Journal of Education <br />for Students Placed At Risk, 13, 106-126. <br />Molfese, V., Molfese, D., Beswick, J., Jacobi-Vessels, J., Molfese, P., <br />Molnar, A., Wagner, M., Haines, B. (2008). Event Related Potentials To <br />Identify Language and Reading Skills. Special Issue on Language and <br />Dyslexia. Topics in Language Disorders, 28, 28 – 45. <br />Molfese, V., Beswick, J., Molnar, A., Jacobi-Vessels, J., &amp; Gozal, D. <br />(2007). The Impacts of Sleep Duration, Problem Behaviors and Health <br />Status on Letter Knowledge in Pre-Kindergarten Children. Child Health <br />and Education: An Interdisciplinary Journal, 1, 41-53. <br />Ferguson, M., Key, A.P.F., Lehman, C., Molfese, D., Molfese V., &amp; Peach, <br />K., (2007). Smoking during pregnancy affects speech processing ability <br />in newborn infants. Environmental Health Perspectives 115, 623-629. <br />Kulakowski, E., Chronister, L., Molfese, V., Slocum, J.M., Studman, C., <br />&amp; Waugaman, P. (2007). International research infrastructure and the <br />impact of export control regulations. Journal of Research Administration, <br />38, 231-240. <br />Molfese, V., Cervelin, J., &amp; Miller, P. (2007). Voice of Experience: <br />Demystifying the NIH Proposal Review Process. Journal of Research <br />Administration, 38, 94-102. <br />33 <br />Endocrinology and Metabolism. In addition, Dr. Moore has been <br />actively involved in presenting his research locally as well as at scientific <br />meetings and though manuscript publications. During 2007-2008 he <br />presented at four separate meetings, published several peer reviewed <br />manuscript and gave several seminars on his research interests. <br />Grants Funded: <br />Role: Principal Investigator <br />Title: Role of PACAP in the Male Fetal Pituitary <br />Funding Agency: NIH/NICHD <br />Total Direct Costs Funded: $209,500 <br />Peer-reviewed Publications: <br />S.J. Winters, D. Ghooray, Y. Fujii, J. P. Moore, Jr., J. R. Nevitt, and S.S. <br />Kakar. Transcriptional Regulation of Follistatin Expression by GnRH in <br />Mouse Gonadotroph Cells: Evidence of a Role for cAMP Signaling. <br />Mol Cell Endocrinol. 2007 Jun <br />15;271(1-2):45-54. Epub 2007 <br />Apr 4. Erratum in: Mol Cell <br />Endocrinol. 2007 Sep 30;276(1- <br />2):88-9. <br />El-Naggar SM, Malik MT, Martin <br />A, Moore JP, Proctor M, Hamid <br />T, Kakar SS. Development of <br />cystic glandular hyperplasia of <br />the endometrium in Mullerian <br />inhibitory substance type <br />II receptor-pituitary tumor transforming gene transgenic mice. J <br />Endocrinol. 2007 Jul;194(1):179-91. <br />Chen YC, Cochrum RK, Tseng MT, Ghooray DT, Moore JP, Winters SJ, <br />Clark BJ. Effects of CDB-4022 on Leydig Cell Function in Adult Male <br />Rats. Biol Reprod. 2007 Dec;77(6):1017-1026. Epub 2007 Aug 22. <br />J.P. Moore, Jr., and S.J. Winters. Weaning and the Developmental <br />Changes in Follicle-Stimulating Hormone, Pituitary Adenylate Cyclase- <br />Activating Polypeptide, and Inhibin B in the Male Rat. Biol Reprod. <br />2008 Apr;78(4):752-60. <br />J. Chanal, C-C Chen, M.J. Rane, J.P. Moore, Jr., M.T. Barati, Y. Song, <br />B.C. Villafuerte. Regulation of Insulin-Response Element Binding <br />Protein-1 in Obesity and Diabetes: Potential Role in Impaired Insulin- <br />Induced Gene Transcription. Endocrinology. 2008 149:4829-36 Epub <br />Jun 19. <br />Research Activities: <br />Dr. Moore’s laboratory is interested in the regulation of pituitary <br />hormones, particularly the sex regulating hormones, the gonadotropins. <br />The gonadotropins, luteinizing hormone (LH) and follicle stimulating <br />hormone (FSH), are both produced and secreted from the same cell <br />type however, the secretion of one gonadotropin often predominates. <br />He has previously observed that the neuropeptide pituitary adenylate <br />cyclase activating peptide (PACAP) differentially affects LH and FSH <br />secretion and subunit gene expression in vitro. He has proposed that <br />PACAP may be important in the normal maturation and function of <br />the pituitary-gonadal axis. He is presently performing investigations <br />designed to evaluate possible roles for PACAP in the development, <br />maintenance and aging of the mammalian reproductive system. <br />Additional research in Dr. Moore’s laboratory is directed toward <br />elucidating the effects of maternal offspring interaction on the onset of <br />puberty in the male. Recent work from his laboratory has determined <br />that manipulations of the transition from suckling to independent <br />feeding for male rats results in differential timing of the initiation of <br />puberty. The change in feeding behavior and/or environment is <br />somehow translated into growth and development of the testes <br />and increased production of the gonadotropins. Future studies are <br />proposed to examine the influences of social interactions and milk <br />borne products on the timing of puberty in the male. <br />In August of 2007, Dr. Moore was awarded his first R01 grant from <br />the National Institutes of Child Health and Development entitled “Role <br />of PACAP in the Male Fetal Pituitary”. The preliminary data presented <br />in his application was obtained through direct funding through the <br />COBRE previously awarded to the Birth Defects Center. In July of 2007, <br />Dr. Moore accepted a faculty position in the Department of Anatomical <br />Sciences and Neurobiology at the University of Louisville School of <br />Medicine and maintains a joint <br />appointment in the Department <br />of Medicine, Division of <br />The pituitary <br />secretes hormones <br />that are essential <br />to growth and <br />reproduction. <br />Assistant Professor <br />Department of Anatomical Sciences <br />and Neurobiology <br />School of Medicine <br />Joseph Patrick Moore Jr., Ph.D. <br />34 <br />Research Activities: <br />Dr. Mukhopadhyay’s principal research focus involves investigation <br />of the role and interaction of various peptide growth factors and <br />transcriptional regulators, whose collective interplay can regulate <br />neural tube and neural crest development, orofacial ontogenesis and <br />palatogenesis. His specific research interests are to examine the role <br />of the nuclear transcriptional regulators (Smads and Ids), coactivators <br />(CBP and p300) and corepressors (c-Ski and Sno) in craniofacial <br />growth and anomalies, to analyze the role of growth factors like TGF-ßs <br />and BMPs in orofacial development as well as characterization of the <br />various transcription factors and their role in normal orofacial growth. <br />Currently, he has been using DNA microarray technology to establish <br />comprehensive “microRNA expression profiles” of developing murine <br />orofacial tissue and of developing neural tube to identify important <br />candidate microRNAs regulating palatogenesis and neural tube <br />development, respectively. In addition, his current projects investigate: <br />(1) BMP signaling (involving BMP receptor specific Smads such as <br />Smad-1, Smad-5 and Smad-8/9) during orofacial development (2) the <br />role of Id (inhibitor of differentiation) -1, Id-2, Id-3 and Id-4 helix-loophelix <br />transcription factors in orofacial ontogenesis <br />and (3) Epigenetics and Fetal Alcohol Syndrome. <br />Grants Funded: <br />Role: Principal Investigator <br />Title: Epigenetics and Fetal Alcohol Syndrome <br />Funding Agency: Kentucky Science &amp; <br />Engineering Foundation <br />Direct Costs Funded: $20,000 <br />Assistant Professor <br />Department of Molecular, Cellular &amp; <br />Craniofacial Biology <br />School of Dentistry <br />Partha Mukhopadhyay <br />Role: Principal Investigator <br />Title: BMP Regulated Transcription in Embryonic Palatal Tissue <br />Funding Agency: The Cleft Palate Foundation <br />Direct Costs Funded: $10,000 <br />Peer-reviewed Publications: <br />Bhattacherjee V, Mukhopadhyay P, Singh S, Johnson C, Philipose <br />JT, Warner CP, Greene RM, Pisano MM. Neural crest and mesoderm <br />lineage-dependent gene expression in orofacial development. <br />Differentiation 75: 463-477 (2007). <br />Marian MJ, Mukhopadhyay P, Borchman D, Tang D, Paterson CA. <br />Regulation of sarco/endoplasmic and plasma membrane calcium <br />ATPase gene expression by calcium in cultured human lens <br />epithelial cells. Cell Calcium. 41:87-95 (2007). <br />Marian M, Mukhopadhyay P, Borchman D, Tang D, Paterson <br />CA. Plasma membrane Ca2+-ATPase isoform expression in <br />human cataractous lenses compared to age matched clear lenses. <br />Ophthalmic Res 40:86-93 (2008). <br />Mukhopadhyay P, Webb CL, Greene RM, Pisano MM. BMP <br />signaling dynamics in embryonic orofacial tissue. J Cell Phys <br />216:771-779 (2008). <br />Marian MJ, Mukhopadhyay P, Borchman D, Tang D and Paterson <br />CA. The effect of hydrogen peroxide on sarco/endoplasmic and <br />plasma membrane calcium ATPase gene expression in cultured <br />human lens epithelial cells. The Open Ophthalmology Journal <br />2:123-129 (2008). <br />35 <br />36 <br />Myers serves also as course director and lecturer of an online Basic <br />Pharmacology course, Neonatal Pharmacology course, and Geriatric <br />Pharmacology course and currently represents the Department of <br />Pharmacology and Toxicology on the University of Louisville School <br />of Medicine Faculty Forum, and serves on the School of Medicine <br />Admissions Committee. <br />Peer-reviewed Publications: <br />Myers, Steven R. and Ali, M. Yeakub. Haemoglobin as a biomarker for <br />tobacco-related nitrosamines, Biomarkers 12(8): 1 – 15, 2007. <br />Myers, S.R., Bioalkylation of Benz(a)anthracene: Implications for <br />Carcinogenesis, Journal of Polycyclic Aromatic Compounds, 27(4): 311 – <br />337, 2007. <br />Myers, S.R., Ali, M. Y., Wright, T., and Cunningham, C. Benzo(a) <br />pyrene Metabolism: Role of Bioalkylation, Journal of Polycyclic Aromatic <br />Compounds 27(4):339 – 359, 2007. <br />Myers, S.R. and Ali, M. Y., Determination of Tobacco Specific Hemoglobin <br />Adducts in Smoking Mothers and NewBorn Babies by Mass Spectrometry., <br />Biomarker Insights 2:269–282, 2007. <br />Myers, S.R. and Spinnato, J.A., Tissue distribution and elimination of N <br />-methyl- N -2,4,6-tetranitroaniline (tetryl) in rats, Archives of Toxicology, <br />81(12): 841-848, 2007. <br />Myers, S.R. and Spinnato, J.A., Metabolism, tissue distribution, and <br />pharmacokinetics of N-methyl-N-2,4,6-tetranitroaniline (tetryl) Environmental <br />Toxicology and Pharmacology, 24(3): 206 -211, 2007. <br />Sumanasekera, W. K., Ivanova, M. M., Johnston, B. J., Dougherty, S. M., <br />Sumanasekera, G. U., Myers, S. R., Ali, M. Y., Kizu, R., and Klinge, C. M., <br />Rapid effects of diesel exhaust particulate extracts on intracellular signaling in <br />human endothelial cells. Toxicology Letters, 174(1-3): 61-73, 2007. <br />Myers, S.R., Zamora, R., Ali, M. Y., Cunningham, C. R., Wright, T., and <br />Weeks, J. Analysis of Polycyclic Aromatic Hydrocarbons in Amniotic Fluid <br />Samples from Smokers and Nonsmokers, Journal of Polycyclic Aromatic <br />Compounds 28(1): 39 – 66, 2008. <br />Myers, S.R., Hurst, H.E., Cunningham, C., Ali. M. Y., and Wright, T., <br />Kinetics of Formation of (±)-anti-7, 8-dihydroxy-9a,10a-epoxy-7, 8, 9, <br />10-tetrahydrobenzo[a]pyrene Adducts with Mouse and Human Hemoglobin, <br />Journal of Polycyclic Aromatic Compounds, 28(2):143 - 164, 2008. <br />Associate Professor <br />Department of Pharmacology &amp; <br />Toxicology <br />School of Medicine <br />Steven Myers <br />Research Activities: <br />Our research examines the development and validation of biological <br />markers of exposure to environmental hazards, including tobacco <br />smoke and automobile exhaust. Specifically, we have developed and <br />refined methods of analysis and utilization of hemoglobin as a biological <br />marker of exposure assessment in individuals exposed to environmental <br />carcinogens. Our research efforts have also led to the application of <br />urine as a biological sample for detection of multiple carcinogens, most <br />notably, the environmentally related polycyclic aromatic hydrocarbons. <br />This research has led to numerous collaborative projects in many polluted <br />areas of the world, including the Czech Republic, and the People’s <br />Republic of China. Over the past number of years, our research has <br />focused on the effects of maternal smoking during pregnancy and we <br />have applied our biomarker techniques to the development of markers of <br />tobacco related carcinogens in both maternal and neonates, especially <br />from mothers that smoke during pregnancy. This research has led to a <br />better understanding of the effects of tobacco smoking on fetal growth <br />and gestation. Further studies are currently ongoing to determine the <br />relationships between maternal and fetal metabolism and detoxification <br />of tobacco carcinogens and the effects of pharmacogenetics of enzyme <br />variation on adduct formation, and gestational age, and neonatal growth. <br />In an extension of these studies, we are also developing the application <br />of amniotic fluid as a biomarker of carcinogen exposure detected in <br />the first trimester of pregnancy and we are developing assays for the <br />detection of breast milk biomarkers that can be applied to women that <br />are breast-feeding their neonates. <br />Dr. Myers has served on numerous NIH as wells as EPA internal as <br />well as external review study sections and panels. He has presented <br />his research extensively both Internationally and throughout the <br />United States. He also lectures in the Pharmacology and Toxicology <br />Medical Student and Graduate Student courses, providing lectures on <br />gastrointestinal pharmacology, local anesthetics, and biomarkers. Dr. <br />37 <br />causes of nearly 70 percent of all birth defects remain unknown. In <br />view of this, the research activities in our laboratory seek to provide a <br />better understanding of the molecular, genetic, and epigenetic basis <br />of normal development, as well as elucidate the genes and molecules <br />that when altered result in the genesis of birth defects and infant low <br />birthweight. Particular focus is centered on prenatal, maternal and <br />child health issues relevant to the state of Kentucky. A combination of <br />unique characteristics in the state, including socio-economic factors <br />and an unusually high percentage of women who continue to smoke <br />and drink during their pregnancy, contribute to an increased prevalence <br />of major birth defects such as oro/facial clefting, neural tube defects, <br />fetal alcohol- and maternal diabetes-induced embryopathies, as well as <br />infant low birthweight and developmental disabilities. <br />Grants Funded: <br />Role: Co-Principal Investigator with Dr. Thomas Knudsen <br />Title: Response Signatures of Alcohol Related Birth Defects <br />Funding Agency: NIH <br />Direct Costs Funded: $221,582 <br />Role: Co-Principal Investigator with Dr. Thomas Knudsen <br />Title: Perinatal Programming of Breast Cancer: Fat and Estrogens <br />Funding Agency: NIH <br />Direct Costs Funded: $104,000 <br />Role: Subproject Director <br />Title: Pre- and Postnatal Tobacco Smoke Exposure: Effects on <br />Neurocognitive Development <br />Funding Agency: NIH <br />Direct Costs Funded: $1,061,826 <br />Role: Principal Investigator <br />Title: Developmental Neurotoxicity of Prenatal Environmental Tobacco <br />Smoke Exposure <br />Funding Agency: University of Louisville Center for Environmental <br />Genomics and Integrative Biology <br />Direct Costs Funded: $30,000 <br />M. Michele Pisano, Ph.D. <br />Professor <br />Department of Molecular, Cellular &amp; <br />Craniofacial Biology <br />School of Dentistry <br />Professor <br />Department of Pharmacology &amp; Toxicology <br />School of Medicine <br />Research Director <br />Laboratory of Molecular Craniofacial <br />Development <br />University Scholar <br />Research Activities: <br />Birth defects and congenital developmental disabilities constitute an <br />underappreciated global pandemic. Eight million infants are born with <br />birth defects each year – nearly forty percent of these infants and <br />children die before the age of 5. Despite unprecedented strides in <br />medicine and healthcare, birth defects remain the leading worldwide <br />cause of infant mortality and childhood morbidity. These statistics <br />notwithstanding, public health efforts in the United States and globally <br />have failed to categorize the prevention and treatment of birth defects <br />as national health priorities. Even international agencies such as the <br />World Health Organization and the United Nations have failed to evolve <br />an appreciation for the magnitude of the human health crisis associated <br />with birth defects and developmental disabilities. In June of 2006, the <br />United Nations General Assembly adopted a declaration urging the <br />nations of the world to strengthen their battle against AIDS – a disease <br />termed by then UN Secretary-General Kofi Annan as the “greatest <br />challenge of our generation”. Indeed, 3 million adults and children die <br />from AIDS annually – a sobering statistic, but one that is exceeded by <br />the 3.3 million infants and children that die annually from birth <br />defects and congenital developmental disabilities. Even in the <br />United States, a country with one of the most advanced healthcare <br />systems in the world, a child is born with a birth defect and two <br />babies with low birthweight – every three minutes. Moreover, despite <br />unprecedented intellectual and technological strides in the biomedical <br />sciences, including sequencing of the human genome and advances <br />in prenatal care/diagnostics – the overall incidence of birth defects <br />and developmental disabilities is not declining and the underlying <br />Role: Co-Investigator <br />Title: Prdm16: Novel Zinc Finger Protein Linked to Palatal Clefting <br />Funding Agency: Kentucky Science and Engineering Foundation <br />Direct Costs Funded: $20,000 <br />Role: Co-Investigator <br />Title: Epigenetics and Fetal Alcohol Syndrome <br />Funding Agency: Kentucky Science and Engineering Foundation <br />Direct Costs Funded: $20,000 <br />Peer-reviewed Publications: <br />Singh S,Yin Y, Pisano MM, Greene RM. Molecular expression profiles <br />of mitogen activated protein kinase signaling pathways in craniofacial <br />development. Birth Defects Res A 79:35-44 (2007). <br />Bhattacherjee V, Mukhopadhyay P, Singh S, Johnson C, Philipose J, <br />Warner C, Greene RM, Pisano MM. Neural crest and mesoderm <br />lineage-dependent gene expression in orofacial development. <br />Differentiation 75:463-477 (2007). <br />Warner D, Horn K, Mudd L, Greene RM, Pisano MM. PRDM16/MEL1: <br />A novel Smad binding protein expressed in murine embryonic orofacial <br />tissue. Biochim Biophys Acta – Molec Cell 1773:814-820 (2007). <br />De Falco M, Pisano MM, De Luca A. Embryology, histology and <br />anatomy of mesothelium. In: Mesothelioma - From benchside to the <br />Clinic; Edit. Baldi, A, Nova Science Publishers, Inc, New York (2007) <br />ISBN 1-60021-789-3. <br />De Falco M, Pisano MM, De Luca A. Signaling involved in epithelialmesenchymal <br />transitions: from embryogenesis to cellular pathogenesis. <br />In: Mesothelioma - From benchside to the Clinic; Edit. A Baldi, A; Nova <br />Science Publishers Inc, New York (2007) ISBN: 1600217893. <br />38 <br />Role: Co-Investigator; PI RM Greene <br />Title: Transcriptional Coactivators and Pregnancy Outcomes <br />Funding Agency: NIH <br />Direct Costs Funded: $1,321,365 <br />Role: Co-Investigator; PI RM Greene <br />Title: Nutritional Epigenetics and Orofacial Development <br />Funding Agency: NIH <br />Direct Costs Funded: $900,000 <br />Role: Co-Investigator; PI D Bayarsaihan <br />Title: Role of TFIIi in Craniofacial Development <br />Funding Agency: NIH <br />Direct Costs Funded: $1,000,000 <br />Role: Principal Investigator, Mentor <br />Title: Nuclear Co-Activators in Developing Craniofacial Tissue <br />Funding Agency: NIH <br />Direct Costs Funded: $410,395 <br />Role: Principal Investigator, Mentor <br />Title: Prenatal Tobacco Smoke Exposure and Hypoxia-Induced <br />Developmental Abnormalities <br />Funding Agency: Philip Morris Research Foundation <br />Direct Costs Funded: $80,000 <br />Esposito ER, Horn KH, Greene RM, Pisano MM. An animal model <br />of in utero cigarette smoke induced growth retardation. Toxicology <br />246:193-202 (2008). <br />Greene, RM, Pisano MM. Chapter 73: Perspectives in orofacial cleft <br />research II: Molecular mechanisms. In Comprehsensive Cleft Care, <br />Edit. Lossee, JE and Kirschner, RE; McGraw-Hill, Ohio (2008) ISBN: <br />9780071481809. <br />Warner DR, Greene RM, Pisano MM. Target Assessment-PRDM16 <br />(MEL1). Current Biodata - Targeted Proteins Database (TPdb) (2008) <br />Available online at http://currentbiodata.com <br />Mukhopadhyay P, Greene RM, Pisano MM. BMP signaling dynamics <br />in embryonic orofacial tissue. J Cell Physiol 216:771-779 (2008). <br />Horn KH, Esposito ER, Greene RM, Pisano MM. The effect of cigarette <br />smoke exposure on the development of Folbp2 null mice. Reprod Tox <br />26:203-209 pp-pp. (2008) <br />39 <br />Research Activities: <br />The research pursued in Dr. Prough’s laboratory focuses on the study <br />of the mechanism of modulation of the enzyme activity of various drug/ <br />carcinogen metabolizing enzymes by various steroid hormones and <br />sterols. For example, Tom Geoghegan and I are studying the effect of <br />dehydroepiandrosterone (DHEA) and its metabolites on regulation of <br />the cytochromes P450; DHEA and DHEA sulfate are major circulating <br />sterols in humans and some primates (5-10 µM concentration). DHEA <br />is also a peroxisome proliferator, but regulates other enzyme systems <br />in addition to those regulated by the peroxisome proliferator activated <br />receptor alpha (PPARa). PPAR and other members of subfamily III <br />of the steroid hormone receptors may interact and modulate their <br />respective action as mediators of the process of gene expression. We <br />have noted that DHEA may alter the phosphorylation status of PPARa <br />and other nuclear receptors by inducing <br />protein phosphatases, specifically protein <br />phosphatase 2A. This action appears <br />to be different that the action of other <br />peroxisome proliferating agents, and <br />may account for the action of DHEA <br />in inducing PPAR target genes. The <br />molecular regulation of PP2A by sterols <br />is understudy. Another collaborative project involves the study of <br />aldehyde toxicity in cardiovascular tissues, in conjunction with Aruni <br />Bhatnagar, Sumanth Prahbu, Sanjay Srivastava, and Stanley D’Souza. <br />Our project studies the metabolism of acrolein, 4-hydroxynonenal and <br />trans-2-hexenal in vascular tissues and how tehse agents regulate of <br />enzyme systems in cardiovascular tissue. In addition, the effects of <br />aldehydes on expression of those cytochromes P450 that metabolize <br />arachidonic acid to various signaling molecules is under study to <br />elucidate how they affect vasoactive action and proliferation and/ <br />or development of vascular smooth muscle and endothelial cells. <br />Aldehydes serve as both substrates for some of these hemoproteins, <br />as well as mechanism-based inactivators of CYP function. The role of <br />aldehyde dehydrogenases and glutathione S-transferases in clearance <br />of aldehydes is also under study, evaluating the various isozymes of <br />these enzymes are regulated in mouse and human. <br />Grants Funded: <br />Role: Project Leader <br />Title: Aldehyde Metabolism and Cardiovascular Disease <br />Funding Agency: NIEHS/NIH <br />Direct Costs Funded: $169,385 <br />Professor <br />Department of Biochemistry &amp; Molecular <br />Biology <br />School of Medicine <br />Russell A. Prough, Ph.D. <br />Dehydroepiandrosterone induces human CYP2B6 through the constitutive <br />androstane receptor, Drug Metabolism and Disposition, 35, 495-501 <br />(2007). [PMID: 17591676; PMCID pending]. <br />D. Conklin, R. Prough and A. Bhatnagar, Aldehyde Metabolism in the <br />Cardiovascular System Molecular Biosystems, 2, 136-150 (2007). <br />V. Tamasi, S. Webb, T. Geoghegan, E. Vila, and R. Prough. PPARalpha <br />Regulation by Dehydroepiandrosterone, In: Proceedings of the 15th <br />International Conference on Cytochromes P450 – Biochemistry, Biophysics <br />and Functional Genomics, Medimond, Bologna, Italy, pp. 23-29 (2007). <br />K.C. Falkner, J.T. Ritter, and R. A. Prough, Regulation of the rat UDPglycosyltransferase <br />1A6 by glucocorticoids involving a cryptic glucocorticoid <br />response element, Drug Metabolism and Disposition, 36, 409-17 (2008) <br />[PMID: 18039810; PMCID pending] <br />V. Tamasi, K.K. Michael Miller, S.L. Ripp, E. Vila, T.E. Geoghegan, and R.A. <br />Prough, Phosphorylaton of Serine 6, 12, and 21 regulates murine PPARa <br />action, Molecular Pharmacology 73, 968-76 (2008) [ PMID: 18079279; <br />PMCID pending]. <br />J. Cai, B.G. Hill, A. Bhatnagar, W.M. Pierce, Jr., and R.A. Prough, <br />Bioactivation and Protein Modification Reactions of Unsaturated Aldehydes, <br />In: Advances in Bioactivation Research (A. Elfarra, Ed.), Springer <br />Science+Business Media, New York, NY IN PRESS (2008). <br />S.J. Webb, K.C. Falkner, T.E. Geoghegan, and R.A. <br />Prough, Convergence of Multiple Nuclear Receptors <br />and Metabolic Signaling Pathways in Xenobiotic <br />and Nutrient Metabolism, In: Volume 2, Cellular <br />and Molecular Toxicology (Ed., Kenneth S. <br />Ramos) of the 2nd Edition of Comprehensive <br />Toxicology (Ed.-Chief, C.A. McQueen), IN <br />PRESS, Elsevier, Oxford, UK (2009). <br />Role: Co-Investigator <br />Title: Molecular Epidemiology of Environmental/Occupational Disease <br />Funding Agency: NIEHS/NIH <br />Direct Costs Funded: $228,552 <br />Role: Co-Principal Investigator <br />Title: NIEHS Summer Environmental Health Sciences Training Program <br />Funding Agency: NIEHS/NIH <br />Direct Costs Funded: $28,725 <br />Role: Mentor <br />Title: NIDDK Summer Endocrinology Research Training Program <br />Funding Agency: NIEHS/NIH <br />Direct Costs Funded: $28,725 <br />Role: Director <br />Title: Career Development of Environmental <br />Health Investigators Project <br />Funding Agency: NIEHS/NIH <br />Role: Investigator <br />Title: DHEA: PPAR-Dependent and Independent <br />Mechanisms of Action <br />Funding Agency: NIH/NIDDK <br />Role: Project Leader <br />Title: University of Louisville’’s Clinical and <br />Translational Science Institute <br />Funding Agency: Translational Technology and Resources <br />Direct Costs Funded: $340,594 <br />Peer-reviewed Publications: <br />K.Cameron Falkner and Russell A. Prough, Regulation of the rat <br />glutathione S-transferase A2 gene by glucocorticoids: Crosstalk through C/ <br />EBPs, , Drug Metabolism Reviews, 39, 371-388 (2007) [PMID: 17786629; <br />PMCID pending]. <br />Amunom, L.J. Stephens, V. Tamasi, D.J. Conklin, A. Bhatnagar, S. <br />Srivastava, M.V. Martin, F.P. Guengerich, and R.A. Prough, Cytochromes <br />P450 catalyze oxidation of a,ß-unsaturated aldehydes, Archives of <br />Biochemistry &amp; Biophysics, 464, 187-96 (2007) [PMID: 17599801; PMCID <br />pending] <br />K. Kohalmy, V. Tamasi, L. Kobori, E. Sarvary, J.-M. Pascussi, P. <br />Porrogi, D. Rozman, R.A. Prough, U.A. Meyer, and K. Monostory, <br />Research Activities: <br />The long-term goal of our research is to understand the molecular and <br />genetic mechanisms that control the differentiation and regeneration <br />of motor neurons and oligodendrocytes, and develop novel molecular <br />strategies for stimulating the de novo regeneration of motor neurons <br />and oligodendrocytes in the injured spinal cord. Research projects <br />include: (1) Identification of the molecular pathways that regulate <br />the early specification and differentiation of motor neurons and <br />oligodendrocytes. (2) Transcriptional and posttranscriptional regulation <br />of homeodomain factors that control the early development of motor <br />neurons and oligodendrocyte cells. (3) Isolation and characterization <br />of the interacting proteins of motor neuron and oligodendrocyte <br />lineage-specific homeodomain transcription factors. (4) Lineagespecific <br />differentiation of embryonic stem cells into motor neurons and <br />oligodendrocytes for spinal cord transplantation. <br />Grants Funded: <br />Role: Principal Investigator <br />Title: Molecular and genetic control of oligodendrocyte development <br />Funding Agency: NIH <br />Direct Costs Funded: $1, 226,157 <br />Role: Principal Investigator <br />Title: Role of Olig3 bHLH transcription factor in gliogenesis <br />Funding Agency: NIH <br />Direct Costs Funded: $338,336 <br />Professor <br />Department of Anatomical Sciences and <br />Neurobiology <br />School of Medicine <br />Matthew Qiu <br />41 <br />Role: Principal Investigator <br />Title: Lineage analysis and signaling mechanism of oligodendrocyte <br />genesis <br />Funding Agency: National Multiple Sclerosis Society <br />Direct Costs Funded: $353, 516 <br />Role: Principal Investigator <br />Title: Role of Olig3 in cerebellar and precerebellar development <br />Funding Agency: NIH <br />Direct Costs Funded: $354,586 <br />Role: Principal Investigator <br />Title: Developmental regulation of axonal myelination by Necl <br />molecules <br />Funding Agency: National Multiple Sclerosis Society <br />Direct Costs Funded: $474,019 <br />Role: Co-Investigator <br />Title: Transcriptional Coactivators and Pregnancy Outcomes <br />Funding Agency: National Multiple Sclerosis Society <br />Direct Costs Funded: $1, 503,187 <br />Peer-reviewed Publications: <br />Liu Z, Hu X, Cai J, Liu B, Peng X, Wegner M, and Qiu M. (2007). <br />Induction of oligodendrocyte differentiation by Olig2 and Sox10: <br />evidence for reciprocal interactions and dosage-dependent <br />mechanisms. Dev. Biol. 302, 683-693. <br />Lee X, Yang Z, Shao Z, Rosenberg SS, Levesque M, Pepinsky RB, <br />Qiu M, Miller RH, Chan JR, Mi S (2007). NGF regulates the expression <br />of axonal LINGO-1 to inhibit oligodendrocyte differentiation and <br />myelination. J. Neurosci. 27, 220-225. <br />Liu B, Liu Z, Chen T, Li H, Peng X and Qiu M (2007). Selective <br />expression of Bhlhb5 in subsets of early-born interneurons and lateborn <br />association neurons in the spinal cord. Dev. Dyn. 236, 829-835 <br />Research Activities: <br />Dr. Sears is Chief Psychologist and Associate Professor of Pediatrics at <br />the Weisskopf Child Evaluation Center. His primary research interest is <br />in autism. In collaboration with other U of L researchers he is involved <br />in studies of cytokines in autism, the neuropsychology of autism, and in <br />medical treatment of autism. <br />Grants Funded: <br />Role: Collaborator <br />Title: Aripiprazole Flexibility Dosed in the Treatment of <br />Children and Adolescents with Autistic Disorder <br />Funding Agency: Bristol-Myers Squibb <br />Direct Costs Funded: $106,486 <br />Role: Collaborator <br />Title: Safety and Tolerability of Aripiprazole Flexibly Dosed in the <br />Treatment of Children and Adolescents with Autistic Disorder <br />Funding Agency: Bristol-Myers Squibb <br />Direct Costs Funded: $92,518 <br />Peer-reviewed Publications: <br />Williams PG, Hersh J, Allard A, &amp; Sears LL. A controlled study of <br />mercury levels in hair samples of children with autism as compared to <br />their typically developing siblings. Res Autism Spectr Disord 2:170-175 <br />(2008). <br />Lonnie Sears, Ph.D. <br />Associate Professor <br />Department of Pediatrics <br />School of Medicine <br />42 <br />Zhang, Y., Shields, L., Pei J., Zhang, Y., Xu, X-M. Hoskins, R., <br />Cai, J., Qiu, M., Magnuson, D., Burke, D., and Shields, C. (2007). <br />The Feasibility of Motor Evoked Potentials, Somatosensory Evoked <br />Potentials, and H-Reflexes Induction in Non-sedated Rodents Using <br />Magnetic Stimulation. J. of Neurosci. Methods. 165, 9-17. <br />Chen X, Qiu M, Whittemore S, Cao Q. (2007). BMP signaling and <br />olig1/2 interact to regulate the differentiation and maturation of adult <br />oligodendrocyte precursor cells. Stem Cell. 25, 3204-3214 <br />Zhao S, Hu X , Park J, Zhu Y, Zhu Q, Luo C, Han R, Cooper N. and <br />Qiu M. (2007). Selective expression of LDLR and VLDLR in myelinating <br />oligodendrocytes. Dev. Dyn. 236, 2708-2712. <br />Li J , Liu Z, Liu Q, Fu X, Cooper N, Pan Y, Li Y , Qiu M*, Shi T*. (2007). <br />Regulatory Network of bHLH Transcription Factors in Mouse Brain. <br />Genome Biology (*co-corresponding authors) 8(11):R244. <br />Hu J., Fu S., Wang Y., Li Y., Jiang X., Wang X, Qiu M., Lu P, Xu X. <br />(2008). PDGF-AA mediates oligodendrocyte lineage differentiation <br />through activation of Erk but not PI3K signaling pathway. Neuroscience, <br />151, 138-147. <br />Liu Z, Li H, Hu X, Yu L, Liu H, Colella R, Mower G , Chen Y, and Qiu <br />M. (2008). Control of precerebellar neuron development by Olig3 bHLH <br />transcription factor. J. Neurosci. 28:101 24-33. <br />Cai J, Zhang Y, Qi Y, Li H, Zhang Y, Han R, Shields CB and Qiu M. <br />(2008). Coordinated expression of Nkx2.2 and Nkx6.2 homeodomain <br />transcription factors in myelinating oligodendrocytes. Glia In revision. <br />Park,J, Liu B, Chen T, Li H, Hu, X, Gao J, Zhu Y, Zhu Q, Qiang B, Yuan <br />J, Peng X and Qiu M. Disruption of Necl-1 cell adhesion molecule <br />leads to delayed axonal myelination in the developing nervous system. <br />J. Neurosci. In press. <br />Research Activities: <br />Dr. Seelan’s principal research interests are in understanding the <br />genetic basis of cognitive and neurodevelopmental disorders such <br />as Autism. One area of active interest is to understand the molecular <br />biology of genes involved in myo-inositol metabolism such as myo- <br />Inositol Synthase and Inositol Monophosphatases 1 and 2. Myo-inositol <br />is an important precursor for the ‘phosphoinositide signaling’ pathway <br />which not only generates IP3, an important second messenger <br />molecule, but also activates several neuronal receptors required for <br />the normal functioning of the brain. Depleted myo-inositol levels are <br />frequently observed in the brains of patients suffering from Autism <br />Spectrum Disorders. Deficiencies in inositol signaling have been <br />implicated in the etiology of several psychiatric disorders including <br />Bipolar Disorder. Specifically, the discovery of novel isoforms for some <br />of these genes in the laboratory has rekindled renewed interest in brain <br />myo-inositol synthesis and regulation, subunit composition of the brain <br />enzymes, and identifying the transcription factors that regulate their <br />expression in brain. Much of this work has been done in collaboration <br />with Dr. R. Parthasarathy, VA Medical Center, Louisville. Another area <br />of interest is the epigenetic modulation of these genes in Autism and <br />other behavioral disorders. A role for CpG methylation in brain-specific <br />regulation has been established for some of these genes and CpG <br />methylation profiles are being <br />developed for normal and affected <br />(Autism) brain tissues to identify <br />critical CpG residues involved <br />in gene expression. Ongoing <br />collaborative studies with Dr. M. <br />F. Casanova, Dept. of Psychiatry <br />and Behavioral Sciences, and <br />Dr. Michele Pisano, Birth Defects <br />Center, University of Louisville, <br />will examine the genetic and <br />biochemical bases for abnormal <br />minicolumns observed in the <br />autistic brain and the effect of <br />environmental stressors such as maternal cigarette smoke exposure on <br />the cognitive abilities of the offspring. His studies are currently funded <br />by the COBRE mechanism and he continues to seek additional funding <br />support for his varied research interests. Funding from the Department <br />of Defense and March of Dimes grant programs are currently pending. <br />Ratnam Seelan, Ph.D. <br />Grants Funded: <br />Role: Sub-project Principal Investigator <br />Title: Effect of interneuron loss on minicolumn structure <br />Funding Agency: National Institutes of Health/National Center for <br />Research Resources; Center of Biological Research Excellence <br />(COBRE) <br />Direct Costs Funded: $120,000 <br />Role: Sub-project Principal Investigator <br />Title: Regulation of Neural Crest Cell Migration <br />by SDF1-CXCR4 signaling <br />Funding Agency: National Institutes of Health/National Center for <br />Research Resources; Center of Biological Research Excellence <br />(COBRE) <br />Direct Costs Funded: $157,000 <br />Peer-reviewed Publications: <br />Seelan RS, Khalyfa A, Lakshmanan J, Casanova MF, Parthasarathy <br />RN. Deciphering the lithium transcriptome: microarray profiling <br />of lithium modulated gene expression in human neuronal cells. <br />Neuroscience 151: 1184-1197 (2008). <br />43 <br />Assistant Professor <br />Department of Molecular, Cellular &amp; <br />Craniofacial Biology <br />School of Dentistry <br />Research Activities: <br />Much of my research activities during 2007-2008 focused on the TGFß <br />and Wnt signaling pathways and their role in developmental processes <br />during formation of the secondary palate. Defects in development of <br />the secondary palate lead to clefts, which affect approximately 1 in <br />700 births. TGFß and Wnt are both large families of cytokines with <br />diverse functions in embryonic and adult tissues. From earlier in vitro <br />studies on primary cultures of embryonic mouse palate mesenchymal <br />cells, we demonstrated that TGFß1 and Wnt-3a cooperate to induce <br />gene transcription. To follow up this observation, we obtained a grant <br />from the American Cleft Palate Foundation to perform high-density <br />microarrays to identify genes whose regulation is uniquely regulated by <br />both TGFß1 and Wnt-3a in combination, using a mouse model, which <br />is very useful because of the similarities to human palate development. <br />Indeed, these experiments have led to a collection of genes that are <br />regulated by TGFß and Wnt, and not seen with either cytokine alone. <br />These data provide a foundation for further analysis of the intersection <br />of these two pathways as it pertains to the normal sequence of events <br />required for proper palate development. We have also performed <br />a comprehensive analysis of the expression of other Wnts in the <br />developing mouse palate, an area that is only now beginning to be <br />explored in detail, and have found several display interesting patterns <br />of expression, suggesting specific roles. We are now in a position to <br />determine the functional role of this large family of proteins. <br />Significant progress has been made on the analysis of a protein <br />identified by us (PRDM16) as being involved in the TGFß signaling <br />pathway, and, when mutated, can lead to cleft palate in mice. There is <br />also evidence in humans linking mutations of PRDM16 to cleft palate. <br />PRDM16 is a transcription factor that has been recently demonstrated <br />to be a protein that can direct cell differentiation. We obtained a grant <br />from the Kentucky Science and Engineering Fund to further study the <br />role of PRDM16 in crucial cellular/developmental processes necessary <br />for proper palate development, such as cell proliferation, synthesis of <br />extracellular matrix, and fusion of the nascent palatal shelves. We are <br />currently in the process of further characterizing the genes regulated by <br />PRDM16 and its possible role in palatal bone formation. <br />Grants Funded: <br />Role: Principal Investigator <br />Title: Gene Discovery in Orofacial Tissue <br />Funding Agency: American Cleft Palate Foundation <br />Direct Costs Funded: $10,000 <br />Assistant Professor <br />Department of Molecular, Cellular &amp; <br />Craniofacial Biology <br />School of Dentistry <br />44 <br />Role: Principal-Investigator <br />Title: PRDM16: A Novel Zinc Finger Protein Linked to Palatal Clefting <br />Funding Agency: Kentucky Science and Engineering Foundation <br />Direct Costs Funded: $18,191 <br />Peer-reviewed Publications: <br />Warner DR, Horn KH, Mudd L, Webb CL, Greene RM, Pisano MM. <br />PRDM16/MEL1: A Novel Smad Binding Protein Expressed in Murine <br />Embryonic Orofacial Tissue. Biochimica et Biophysica Acta-Molecular <br />Cell Research 1773:814-820 (2007). <br />Warner DR, Greene RM, Pisano MM. (2007) “PRDM16-Target <br />Assessment” Targeted Proteins Database. <br />P. Mukhopadhyay P, Webb CL, Warner DR, Greene RM, Pisano MM <br />“BMP Signaling Dynamics in Embryonic Orofacial Tissue. Journal of <br />Cellular Physiology 216:771-779 (2008). <br />Warner DR, Smith IV HS, Webb , Greene RM, Pisano MM “Expression <br />of Wnts in the Developing Murine Secondary Palate” International <br />Journal of Developmental Biology, in press. <br />Dennis Warner <br />45 <br />Research Activities: <br />Dr. Wittliff’s team explores the roles of hormones and their mimics in <br />human cancer, exploiting proteomics and genomics. He was among <br />the first to prove appearance of estrogen receptors in breast cancer <br />predicted a patient’s response to hormone therapy. This finding led <br />to collaborations with the National Surgical Adjuvant Breast Project, <br />establishing Tamoxifen as adjuvant therapy for breast cancer and use of <br />receptors as tissue biomarkers of a patient’s prognosis and response. <br />Wittliff’s discovery of receptor polymorphism in cancer provided <br />evidence of another receptor isoform, confirmed recently as ER-beta. <br />With NEN/DuPont, Dr. Wittliff developed the original FDA-approved kits <br />for assessing receptors in biopsies, celebrated as a major contribution <br />to laboratory medicine. His laboratory in the Brown Cancer Center was <br />designated the National Reference Facility for performing QA surveys <br />of receptor testing for historic clinical trials in North America. Focusing <br />expertise on other molecules exhibiting estrogen mimicry, Dr. Wittliff <br />and IA, Inc. patented receptor-based biosensors detecting endocrinedisrupting <br />compounds in the environment. <br />In recognition of contributions to medicine, the University of Innsbruck, <br />Austria awarded him, Doctor of Medicine honoris causa. More than <br />200 students and research fellows have trained in Dr. Wittliff’s program <br />in the Hormone Receptor Laboratory. He has received the Award for <br />Outstanding Contributions to Clinical Chemistry in a Selected Area of <br />Research from the American Association for Clinical Chemistry and <br />was given the Distinguished Scientist’s Award by the Clinical Ligand <br />Assay Society. In 2004, the American Cancer Society recognized his <br />lifetime achievements with the Goldsmith Research Excellence Award. <br />Recently, Dr. Wittliff served as Visiting Industry Professor at Arcturus <br />Applied Genomics, where research on the genomics of human breast <br />cancer using laser capture microdissection revealed clinically relevant <br />molecular signatures. These latest discoveries and his development of <br />a unique Tumor Marker Database and biorepository have resulted in the <br />filing of numerous new patents for the University of Louisville and the <br />licensing of his technologies. <br />Grants Funded: <br />Role: Principal Investigator <br />Title: A Genomic Approach for Assessing Clinical Outcome of Breast <br />Cancer using Cells Isolated by Laser Capture Microdissection <br />Funding Agency: Phi Beta Psi Sorority Research Foundation <br />Direct Costs Funded: $47,250 <br />Professor <br />Department of Biochemistry &amp; Molecular <br />Biology <br />Research Professor of Surgery <br />School of Medicine <br />James L. Wittliff, Ph.D., M.D. <br />Research Activities: <br />Amy I. Whitsel, MD is an active <br />clinician in the division of Maternal- <br />Fetal Medicine in the Department <br />of Obstetrics and Gynecology <br />who has board certifications in <br />Obstetrics and Gynecology <br />and Maternal-Fetal Medicine. <br />Her clinical and research interests <br />are in the prevention, detection and <br />management of pregnancies complicated by <br />congenital anomalies. Her undergraduate background <br />is in cell and developmental biology and her fellowship research was <br />in the teratogenic effects of valproic acid working with the chicken <br />embryo in ovo model. She enjoys assisting patients and families with <br />complicated pregnancies, coordinating the specialized care of the <br />fetus and neonate with congenital anomalies and inherited disorders <br />and regularly works with the Fetal Board <br />at Kosairs Childrens Hospital. She <br />is interested in collaborating in <br />research projects looking at the <br />causes of birth defects and <br />prevention. <br />Assistant Professor <br />Department of Obstetrics &amp; Gynecology <br />Division of Maternal – Fetal Medicine <br />School of Medicine <br />Amy I. Whitsel, M.D. <br />46 <br />Role: Principal Investigator <br />Title: The Proof of Concept Grant <br />Funding Agency: Office of Technology Transfer <br />Direct Costs Funded: $25,000 <br />Role: Co-Principal Investigator <br />Title: Genomic Approach to Predicting Breast Cancer Recurrence <br />Funding Agency: Brown Cancer Center Pilot Project 2006 <br />Direct Costs Funded: $37,750 <br />Peer-reviewed Publications: <br />Wittliff JL, Kruer TL, Andres SA, Smolenkova IA. Molecular Signatures <br />of Estrogen Receptor-associated Genes in Breast Cancer Predict <br />Clinical Outcome. In : Hormonal Carcinogenesis V (Li JJ, Li SA, Mohla <br />S, Rochefort H, Maudelone T, Eds.), Springer Verlag, pp.349-357, 2008. <br />Kerr II, DA, Eliason JF, Wittliff JL Steroid Receptor and Growth Factor <br />Receptor Expression in Human Non-small Cell Lung Cancers Using <br />Cells Procured by Laser-Capture Microdissection. In : Hormonal <br />Carcinogenesis V (Li JJ, Li SA, Mohla S, Rochefort H, Maudelone T, <br />Eds.), Springer Verlag, pp.377-384, 2008. <br />Andres, S.A., Kerr II, D.A., Bumpus, S.B., Kruer, T.L., Thieman, J.W., <br />Smolenkova, I.A., Wittliff, J.L. A Three-Tiered Approach for Calibration <br />of a Biosensor to Detect Estrogen Mimics. Adv Exp Med Biol, 614:305- <br />313, 2008. <br />Wittliff, JL, Andres SA, Kruer TL, Kerr II, DA, Erb JL Biosensors and <br />Molecular Signatures: Detecting Estrogen-like Therapeutics &amp; Predicting <br />Clinical Outcome of Cancer. Adv Exp Med Biol, 315-322, 2008. <br />Role: Principal-Investigator <br />Title: University of Louisville component, Commercialization of <br />Nutraceuticals to Enhance Sustainable Agriculture in Limited Resource <br />Caribbean Farming Communities <br />Funding Agency: USAID/Clemson University <br />Direct Costs Funded: $97,306 <br />Role: Core Faculty/Recruiter <br />Title: <br />Funding Agency: National Institutes of Health, <br />Cancer Education Grant Program, NCI <br />Direct Costs Funded: $356,665 <br />Role: Investigator <br />Title: Podocytes and Oxidative Stress in Diabetic Kidney <br />Funding Agency: National Institutes of Health <br />Direct Costs Funded: $96,728 <br />Role: Principal Investigator <br />Title: Gene Expression Profiling of Human Lung Cancer Cells Isolated <br />by Laser Capture Microdissection <br />Funding Agency: Kentucky Lung Cancer Research Program <br />Direct Costs Funded: $271,845 <br />Role: Principal Investigator <br />Title: Optimization of a Comprehensive Database with Tissue <br />Processing and Evaluation for Genomic &amp; Proteomic Analyses <br />Funding Agency: Asterand, Inc. <br />Direct Costs Funded: $105,000 <br />Cara Cashon, Psychology &amp; Brain <br />Science, College of Arts &amp; Science <br />Ken Ramos, Biochemistry &amp; <br />Molecular Biology, School of Medicine <br />Paul Tiwana, Oral &amp; Maxillofacial <br />Surgery, School of Dentistry <br />Stephen J. Winters, Division <br />of Endocrinology, Metabolism &amp; <br />Diabetes, School of Medicine <br />Photos were not avavilable for these members: <br />Joe Hersh, Pediatrics, School of Medicine <br />Carolyn Mervis, Psychology &amp; Brain Science, College of Arts <br />&amp; Science <br />Rachel Neal, Environmental &amp; Occupational Health Science, <br />School of Public Health <br />Jerry Rabalais, Pediatrics, School of Medicine The Birth Defects Center acknowledges Heather L. <br />Jones, University of Louisville Design and Printing <br />Services, for graphic design on this document. <br />Other Members of the Birth Defects Center <br /> The University of Louisville is an equal opportunity institution and does not discriminate against persons on the basis of race, age, religion, sex, disability, color, sexual <br />orientation, national origin or veteran status. <br />This publication was prepared by the University of Louisville and printed with state funds KRS 57.375. 167339 – 01/09 <br />Notes <br />Birth Defects Center <br />501 S. Preston Street, Suite 301 <br />Louisville, Kentucky 40292 <br />502.852.7507 • 502.852.4702 <br />www.louisville.edu/hsc/birthdefectscenter/index.htm</p>