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Bienn report full text

Biennial Report 2009-2010


Director’s Statement
Nothing in Nature is more fascinating than the development of a complex, multicellular organism that progressively acquires the essential attributes of its parents. When one considers the complexity of molecular, cellular and tissue interactions that are necessary to orchestrate embryonic development, one must indeed be amazed at Nature’s handiwork. However, despite the fact that most infants are born normal— In a country that can boast of the best health care system in the world— every three minutes there is a baby born with a birth defect. Each year, in the United States alone, at least 120,000 babies are born with major structural birth defects. in addition, one in eight babies is born too soon. Premature birth is the number one cause of infant mortality— with nearly 20% of all infant deaths due to complications attendant to congenital anomalies.
For the past 50 years, scientists have pursued fundamental knowledge about the developing embryo and application of that knowledge to reduce the burden of disabilities. The current mantra for contemporary research addressing the causes of congenital malformations is one that strives for “bench to bassinet” outcomes. Biomedical advances are increasingly being made by research teams, using interdisciplinary approaches and supported by open access to powerful databases and online tools. In the last decade, biomedical and research breakthroughs, notably in genetics and stem cells, have helped transform the care of children and have improved both diagnosis and treatment for numerous diseases. These breakthroughs have included advances in newborn screening for inborn errors of metabolism; early diagnosis of primary immunode.ciencies; stem cell therapeutics for childhood neurological diseases; prenatal stem cell transplantation; and improved diagnosis of genetic disease in preimplantation embryos. To be sure, .ve Nobel Prizes in Physiology or Medicine in the past decade alone have had a profound effect on enlarging our understanding of embryonic development. In 2001 the award was given for discoveries of key regulators of the cell cycle, whereas the 2002 award recognized discoveries concerning genetic regulation of organ development and programmed cell death. In recent years the Nobel committee paid tribute to the discovery of RNA interference-gene silencing (2006) and the ellucidation of principles for introducing speci.c gene modi. cations in mice by the use of embryonic stem cells (2007). Most recently, the prize was awarded for the development of in vitro fertilization (2010).
“Science is facts; just as houses are made of stone, so is science made of facts; but a pile of stones is not a house, and a collection of facts is not necessarily science.”
— Jules Henri Poincaré (1854-1912) French mathematician.
A pediatrician who practiced in the 1950s would not recognize the children’s health care landscape today: babies born three month too soon and weighing less than 1 1/2 lb survive; diseases such as polio and bacterial meningitis that often killed or crippled children are so rare that most physicians have never treated them; new imaging technologies provide powerful prenatal diagnostic tools to enable identi. cation of birth defects in utero; fetuses are now operated on for life-threatening disorders; expectant mothers are treated with drugs and vitamins to prevent certain birth defects. What all these advances have in common is that they were made possible by biomedical research—the very types of research being conducted within the University of Louisville Birth Defects Center.
The remarkable successes of biomedical research notwithstanding, the frequency of congenital craniofacial anomalies remains distressingly high. Despite an impressive broadening of our understanding of the molecular machinery orchestrating embryonic development, the fundamental mechanisms governing growth and development of the embryo remains poorly de.ned. When depicting far-off lands at the edge of the known world, maps from the Middle Ages declared “Here There Be Dragons.” Although our understanding of the molecular mechanisms that coordinate development of the embryo/fetus has dramatically increased in the past several decades, our knowledge remains uncomplicated by a full appreciation of the regulatory intricacies involved in normal, much less abnormal, development. Here there be dragons indeed!
“It is a capital mistake to theorise before one has data. Insensibly one begins to twist facts to suit theories instead of theories to suit facts.”
— Arthur Conan Doyle (1859-1930) British physician and novelist.

While many examples of individual research support can be acknowledged (see individual faculty pro.les that follow), two organizations require singular recognition:
1) Each year Kosair Charities (www. kosair.org) donates millions of dollars to help support health care organizations in Kentucky and southern Indiana that specialize in treating children. During the past several years, the University of Louisville Birth Defects Center received signi.cant support from Kosair Charities. On behalf of the University and the Center, I wish to acknowledge this support, which has made an important and positive impact on our ability to address the missions of the Center.
2) For the past eight years the National Center for Research Resources (http://www.ncrr.nih.gov) at the NIH has supported a Center of Biomedical Research Excellence (COBRE) whose purpose was to foster interdisciplinary, health-related research aimed at illuminating the molecular etiologies of developmental defects and disabilities, and to enhance the competitiveness of junior investigators for independent funding. Because of success in achieving these goals, the COBRE was refunded by the NCRR in 2008 for an additional .ve years in the amount of $8.8 million.
“Science is organized common sense, where many a beautiful theory was killed by an ugly fact.”
— Thomas Huxley (1825-1895) British biologist



Distinguished University Scholar Professor and Chair, Department of Molecular, Cellular and Craniofacial Biology School of Dentistry Associate, Dept. Pediatrics Director, Birth Defects Center University of Louisville


David Adamkin, M.D.
Professor Department of Pediatrics Director Neonatal Fellowship Program
Director Division of Neonatal Medicine Director Neonatal Nutrition Research

Program
Dr. Adamkin’s research interest is in Neonatal Nutrition. He has authored over 87 articles, 29 book chapters and 4 books dealing with methods and strategies to nourish premature infants. This includes research in infant formula develop­ment and human milk. He teaches nutrition to neonatologists nationally for the American Academy of Pediatrics and also lectures annually in Europe. Among his most recent accomplishments: a six-year appointment to the Committee on Fetus and Newborn for the American Academy of Pediatrics; Neonatal Nutritional Books and Pocket Manuals published in English as well as Polish and; in 2009, Dr. Adamkin received a Honoris Causa Doctorus from Poznan University of Medical Sciences in Poland.


Grants Funded:
Role: Principal Investigator Title: Fetal and Infant Mortality Review (FIMR) Funding Agency: Adult and Child Health Improvement, Cabinet for Health Services: Department of Public Health and Family Services Direct Costs Funded: $20,000
Role: Co-Principal Investigator Title: Study of Talactoferrin for Nosocomial Infection in Preterm Infants Funding Agency: Agennix Direct Costs Funded: $467,844
Role: Co-Principal Investigator Title: Human Milk Analysis for Infants in the NICU Funding Agency: WHAS Crusade for Children Direct Costs Funded: $55,000

Peer Review Publications:
Radmacher PG, Lewis SL, Adamkin DH. Early Amino Acids and the Meta­bolic Response of Extremely Low Birth Weight Infants (<1000 g) in Three Time Periods. Journal of Perinatology. 29(6):433-7, June 2009.
Adamkin DH. Late Preterm Infants: Severe Hyperbilirubinemia and Postna­tal Glucose Homeostasis. Journal of Perinatology. 29(2); S12-S7, May 2009.
Bull MJ, Engle WA, The Committee on Injury, Violence, and Poison Preven­tion and Adamkin DH (COFN). Safe Transportation of Preterm and Low Birthweight Infants at Hospital Discharge. Pediatrics, 123(5);1424-1429, May 2009.
Stark AR, Adamkin DH, Baley JE, Bhutani VK, Carlo WA, Kumar P, Polin RA, Tan RC, Watterberg KL (COFN). Advanced Practice in Neonatal Nursing. Pediatrics, 123(6);1606-1607, June 2009.
Brion L, Adamkin DH, Bancalari E, Guttentag S, Cummings J, Jule S, RyanR, Neu J. Commentary: Resident Duty Hour Restrictions: Is Less ReallyMore? Journal of Pediatrics, 154(5):631-632, May 2009.
Stark AR, Adamkin DH, Baley JE, Bhutani VK, Carlo WA, Kumar P, Polin RA, Tan RC, Watterberg, KL (COFN). Policy Statement- Hospital Stay forHealthy Term Newborns. Pediatrics, 125(2);405-409, February 2010.
Kumar P, Denson SE, Mancuso TJ, Committee on Fetus and Newborn Ad­amkin DH. Clinical Report- Premedication for Nonemergency EndotrachealIntubation in the Neonate. Pediatrics, 125(3):608-615, March 2010.
Watterberg KL, Adamkin DH, Baley JE, Carlo WA and Committee on Fetus and Newborn. Policy Statement-Postnatal Corticosteroids to Prevent or Treat Bronchopulmonary Dysplasia. Pediatrics, 126(4);800-808, October 2010.
Adamkin DH, Radmacher PG, Lewis S. Nutrition and Selective Disorders of the Gastrointestinal Tract. Care of the High-Risk Neonate, 6th edition, Klausand Fanaroff, W.B. Saunders, November 2010.
Adamkin DH, Advances in Neonatal Nutritional Care. In Bhatia, J and Oom­men, M(eds.). Innovations in Neonatal Perinatal Medicine: World Scienti.c Publishing Company, In Press, 2009.
Adamkin DH, Commentary on Bovine Lactoferrin for prevention of lateonset sepsis in VLBW infants, a randomized trial. In Press, May 2010.

Books Written:
Adamkin DH. Nutritional Strategies for the Very Low Birthweight Infant. Cambridge University Press, copyright 2009.

Webinars/Educational Videos:
Adamkin DH, Ehrenkranz R, Zeigler E. Webinar; Nutrient Enrichment High Protein Strategies. Abbott Nutritional, New York, NY, February 2009.Adamkin DH (Course Director), Ehrenkranz R, Zeigler E. National EducationVideos; Improving Outcomes in Preterm Infants with Nutrition Series. New York, NY, February 2009.
Adamkin DH, Promoting Nutritional Outcome in Premature Infants: Optimiz­ing Protein. Director: Medical Speaker Content Development Meeting to Train Nutritionists and Neonatologists on Teaching Protein and Neurodevelopmental Outcomes. Dallas, TX, March 2009.
Adamkin DH (Course Director), Ehrenkranz R, Zeigler E. ImprovingOutcomes in Preterm Infants with Nutrition Series. 6 Webinars, Broadcast throughout the USA, April 2009.
Adamkin DH and COFN, The Hypoglycemia Screening Management and Guideline for the American Academy of Pediatrics. Pediatrics, Submitted, April 2010.
Adamkin DH, Invited Faculty. Webinar; Necrotizing Enterocolitis: Controver­sies and Evolving Therapies. Case Western Reserve University, Cleveland, OH, June 2010.
Adamkin DH, Invited Faculty. Nestle Nutrition Institute Website video, Feed­ing Strategies. Palo Alto, CA, July 2010.

External Professional Activities:
•
Committee on Fetus and Newborn, American Academy of Pediatrics

•
Editorial Board, Journal of Perinatiology

•
National Advisory Board, Allere

•
Reviewer for Guidelines for Perinatal Care, American Academy of Pediatrics

•
Editorial Board, Archives of Perinatal Medicine, Polish Society of Perinatal Medicine

•
Chairperson VIII Winter School on Perinatal Medicine, Zermatt, Switzerland

•
Dr. Thomas H. Pauly Lectureship & Service Award, KY Perinatal Association, 2009.

•
Dr. Patricia Nicol Lectureship, KY Perinatal Association,2010.

•
Best Doctors in America List, 2009-2010

•
International Association of Pediatricians, Top Pediatrician in Louisville, 2010.


The white matter consists mainly of myelinated axons, which is distributed into some speci.c areas including spinal cord, prefrontal cortex, corpus callosum, limbic system, and cerebellum etc. It plays an indispensable function not only on motor movement but advanced neuro-behaviors as well, such as self-discipline, judgment, problem solving, emotional management, long-term memory, and coordination. Both extrinsic and intrinsic cues that impact on either the developing process or the developed architecture will lead to the neurological disorders. The research activities in Dr. Cai’s lab focus on understanding molecular, genetic and epigenetic regulations of white matter development in the CNS as well as pathological mechanisms in white matter impairment. The myelin-forming process and oligodendroglial-axonal interaction are targeted by use of genetic, molecular and cellular approaches on the mouse models resembling human CNS development or neurological diseases. The study aims: (1) to identify and characterize candidate genes that are speci.cally expressed in neurons or glias; (2) to investigate the ‘molecular switch’ in the CNS that are involved in white matter injury; (3) to develop molecular and/or cellular strategies for preventive or therapeutic purpose.

Grants Funded:
Role: Principal Investigator Grant Title: Phenotype on myelination and myelin Architecture in intermittent hypoxia mouse model Funding Agency: University of Louisville School of Medicine Direct Costs Funded: $14,964.15
Role: Principal Investigator Grant Title: Vulnerability of defective myelin to intermittent hypoxia during sleep Funding Agency: Sleep Research Society Foundation/J. Christian Gillin,
M.D. Research Grant Direct Costs Funded: $20,000
Role: COBRE Supported Junior Investigator Grant Title: Intermittent hypoxia-mediated oligodendrocytes defects in a murine model of gestational sleep apnea Funding Agency: NIH/NCRR, COBRE Direct Costs Funded: $100,000

Jun Cai, M.D., Ph.D.
Assistant Professor
Department of Pediatrics School of Medicine



Publications:
Fu, H., Cai, J., Clevers, H., Fast, E., Gray, S., Greenberg, R., Jain, M., Ma, Q., Qiu, M., Taylor, C., and Stiles, C.D. A genome-wide screen for spatially restricted expression patterns identi.es transcription factors that regulate glial development. Journal of Neuroscience 29: 11399-11408 (2009).
Cai, J., Zhu, Q., Zheng, K., Li, H., Qi, Y., Cao, Q., and Qiu, M. Co-localization of Nkx6.2 and Nkx2.2 homeodomain proteins in differentiated myelinating oligodendrocytes. Glia 58(4): 458-468 (2010).
Zhang, Y.J., Zheng, Y., Zhang Y.P., Shields, L.B.E., Hu, X., Yu, P., Burke, D.A., Wang, H., Cai, J., Byers, J., Whittemore, S.R., and Shields, C.B. Enhanced adenoviral gene delivery to motor and dorsal root ganglion neurons following injection into demyelinated peripheral nerves. Journal of Neuroscience Research (2010) (in press).

External Professional Activities:
Ad hoc reviewer:
Neurobiology of Disease, Stem Cells and Development. 2010 Science Advisory Board, BIT’s 1st Annual World Congress of NeuroTalk 2010



Guy Brock, Ph.D.
Assistant Professor
of Bioinformatics & Biostatistics School of Public Health
My main area of methodological research is in statistical bioinformatics and statistical genetics, with focus on the areas of cluster validation, missing value imputation, and classi.cation for high-throughput data. I have also worked on
methods for miRNA expression and gene methylation data.



Grants Funded:
Clinical & Translational Science Pilot (Kidd, LR) 7/1/10-6/30/11 Intramural $49,980
Innate Immune Response Predictors of Prostate Cancer Outcomes
Description: We propose to systematically identify and validate joint modifying effects of 192 innate immunity-related single nucleotide polymorphisms (SNPs) in relation to PCa risk and disease prognosis. A case-cohort will be used to evaluate whether patients who inherit compromised innate immunity markers will suffer shortened disease-free relapse and even death. Role: Co-Investigator
1RC2AA019385-01 (McClain, C) 09/01/09-08/31/11 2.4 Calendar NIH $1,618,051 (project total costs)
Biomarkers for Steatohepatitis
Description: The purpose of this project is to address the following questions: 1) Are there biomarkers determined by proteomics/metabolomics that are common to ASH, NASH and TASH that indicate mechanistic commonalities in steatohepatitis?; 2) Are there unique biomarkers for ASH compared with NASH/TASH?; and 3) Are there biomarkers for ASH that predict prognosis/outcomes? Role: Co-Investigator. Dr. Brock will analyze experimental data and provide statistical and computational support.
10EM00542 (Rouchka, E and Kalb. eisch, T) 01/01/10-12/31/11
1.8 Calendar DOE $951,501 (project total costs)
Extension of Informatics Infrastructure to Support Translational and Basic Research
Description: The purpose of this project is to build the bioinformatics infrastructure and research pro.le of the University of Louisville, by providing support for junior investigators in the area of bioinformatics at the university. The project also supports the development of bioinformatic software tools, which can be used by other investigators at the university to improve their bioinformatics-oriented research. Role: Co-Investigator. Dr. Brock will develop methods and software tools for the integrated analysis of miRNA and mRNA expression data, and apply these methods to data from mouse embryonic tissue collected during neural tube development.
P20RR017702 (Greene, RM) 09/30/02-05/31/13 1.8 Calendar NIH / NCRR $297,367 (core only)
Molecular Determinants of Developmental Defects
This program, led by Robert M. Greene, Ph.D., an established biomedical research scientist, well recognized for his extensive expertise central to the research theme of the proposal-molecular mechanisms underlying developmental defects, will 1) substantially enhance the research career development and research competitiveness of no less than .ve (5) junior investigators, two early career investigators, and one senior investigator, and 2) promote the development and enhance the evolution of our Center such that it will be able to successfully compete for independent Center and/or program project funding. Role: Co-Investigator. Dr. Brock will analyze experimental data and provide statistical and computational support.
P30 ES014443 (Ramos) 04/01/07 – 03/31/11 1.8 Calendar NIH / NIEHS $600,000 (core only)
Center for Environmental Genomics and Integrative Biology Bioinformatics, Biostatistics and Computational Biology Core
The role of this core is to provide center members with assistance and support of research in the areas of informatics, biostatistics, and systems modeling. Other goals include providing education and training and promoting discovery and collaboration with the center members and junior investigators in the areas of genomics and integrative biology. Role: Statistical Consultant
R01HD053509 (Greene, RM) 12/01/07-11/30/12 0.8 Calendar NIH $255,546
Transcriptional Coactivators and Pregnancy Outcomes
The overall hypothesis to be tested by this proposal is that normal CNS development in the mammalian embryo requires folate-mediated activation of a transcriptional complex, functionally dependent on proper expression and integration of speci.c transcriptional coactivators. Role: Co-Investigator. Dr. Brock will analyze experimental data and provide statistical and computational support. Does involve human subjects. Does involve vertebrate animals.
R01DE018215 (Greene, RM) 04/01/09-03/31/14 0.8 Calendar NIH $250,000
Nutritional Epigenetics and Orofacial Development
This study will investigate whether folate de.ciency can disrupt the normal methylation state of speci.c candidate genes and contribute to development of orofacial clefts in mice embryos. Role: Co-Investigator. Dr. Brock will analyze experimental data and provide statistical and computational support.

Publications:
2010
Oh S, Kang D, Brock GN, and Tseng GC. “Biological impacts of missing value imputation on down-stream analyses in microarray data”, Bioinformatics 2010 Nov 02 [Epub ahead of print].
Warner DR, Mukhopadhyay P, Brock GN, Pihur V, Pisano MM, and Greene RM. “TGFß and Wnt-3a interact to induce unique gene expression pro. les in murine embryonic palate mesenchymal cells”, Reproductive Toxicology, 2010 Oct 15. [Epub ahead of print].
Cave M, Appana S, Patel M, Falkner C, McClain C, and Brock G. Polychlorinated Biphenyls, Lead, and Mercury Are Associated with Liver Disease In American Adults: NHANES 2003-2004. (accepted to Environmental Health Perspectives)
Ouseph R, Eng M, Ravindra K, Brock GN, Buell JF, Marvin MR. Review of the use of hepatitis B core antibody positive kidney donors Transplantation Reviews (Orlando). 2010 Jul 22. [Epub ahead of print].
Arnold F, Brock GN, Peyrani P, Rodrguez E, Fuenzalida AD, Rossi P, and Ramirez JA. Time to clinical stability in hospitalized patients with community-acquired pneumonia: predictive accuracy of the PSI vs. CRB-65. Respiratory Medicine 2010 Jun 22. [Epub ahead of print]
Kidd LR*, Brock GN*, Vancleave TT, Benford ML, Lavender NA, Kruer TL, Wittliff JL. Angiogenesis-associated Sequence Variants Relative to Breast Cancer Recurrence and Survival. Cancer Causes & Control 21:1545-1557 (2010).
Mukhopadhyay P, Brock G, Pihur V, Webb C, Pisano MM, Greene RM. Developmental microRNA expression pro.ling of murine embryonic orofacial tissue. Birth Defects Research Part A: Clinical and Molecular Teratology 88:511-34 (2010).
Spiller HA, Appana S, Brock GN. Epidemiological trends of suicide and attempted suicide by poisoning in the US: 2000 – 2008. Legal Medicine, 12:177-83 (2010).
Chen Y, Brock G, Wu D. Estimating Key Parameters in Periodic Breast Cancer Screening Using the Canadian National Breast Screening Study Data. Cancer Epidemiology 34:429-33 (2010).
Eng M, Brock G, Li X, Chen Y, Ravindra KV, Buell JF, Marvin MR. Perioperative Anticoagulation and Antiplatelet Therapy in Renal Transplant: Is There an Increase in Bleeding Complication? Clinical Transplantation, 2010 Jun 7. [Epub ahead of print]
VanCleave TT, Moore JH, Benford ML, Brock GN, Kalb. eisch T, , Baumgartner RN, Lillard JW, Kittles RA, Kidd LR. Interaction among variant vascular endothelial growth factor (VEGF) and its receptor in relation to prostate cancer risk. The Prostate 70:341-52 (2010).
Cave M, Falkner KC, Ray M, Joshi-Barve S, Brock G, Khan R, Bon Homme M, and McClain C. Toxicant-associated steatohepatitis in vinyl chloride workers. Hepatology 51:474-81 (2010).
Lavender NA, Komolafe OO, Brock GN, Moore JH, VanCleave TM, Srivastava DS, Benford M, States JC, Kittles RA, and Kidd LR. No association between variant DNA repair genes and prostate cancer risk among men of African descent. The Prostate 70:113-9 (2010).
2009
Aliberti S, Brock GN, Peyrani P, Blasi F, Ramirez JA, and the CAPO Study Group. The pneumonia severity index and the CRB-65 in cancer patients with community-acquired pneumonia. International Journal of Tuberculosis and Lung Disease 13:1550-1556 (2009).
Myers J, Brock G, Appana S, and Gray L. Kentucky pilot project for primary PCI without onsite CABG. Journal of the Kentucky Medical Association 107:451-8 (2009).
Lavender NA, Benford M, VanCleave TT, Brock GN, Kittles RA, Moore JH, Hein DW, and Kidd LCR. Examination of polymorphic glutathione S-transferase (GST) genes, tobacco smoking and prostate cancer risk among men of African descent: a case-control study. BMC Cancer 9:397 (2009).
Arnold FW, LaJoie AS, Brock GN, Peyrani P, Rello J, Menéndez R, Lopardo G, Torres T, Rossi P, Ramirez JA, and the CAPO investigators. Improving Outcomes in Elderly Patients with Community-Acquired Pneumonia by Adhering to National Guidelines: Community-Acquired Pneumonia Organization International Cohort Study Results. Archives of Internal Medicine 169:1515-24 (2009).
Woodall CE, Brock GN, Byam JA, Scoggins CR, McMasters KM, and Martin RC. An evaluation of 2,537 gastrointestinal stromal tumors for a proposed clinical staging system. Archives of Surgery 144:670-8 (2009).
Brock GN, Beavis WD, and Kubatko LS. Fuzzy logic and alternate methods as a screening tool for detecting gene regulatory networks. Information Fusion 10:250-259 (2009).
Marvin MR*, Brock GN*, Kwarteng K, Nagubandi R, Ravindra KV, Eng M, and Buell JF. Increasing utilization of human T-cell lymphotropic virus(+) donors in liver transplantation: is it safe? Transplantation 87:1180-1190 (2009).
Xu P, Brock GN, and Parrish RS. Modi.ed linear discriminant analysis approaches for classi.cation of high-dimensional microarray data. Computational Statistics and Data Analysis 53:1674-1687 (2009).
Landry CS, Brock G, Scoggins CR, McMasters KM, and Martin RC. A Proposed Staging System for Gastric Carcinoid Tumors Based on an Analysis of 1,543 Patients. Annals of Surgical Oncology 16:51-60 (2009).
* These authors contributed equally to this work
PEER-REVIEWED BOOK CHAPTERS
Pihur V, Brock GN, Datta S, and Datta S. “Cluster validation for microarray data: An appraisal”. In Indian Statistical Institute Platinum Jubilee Series, Statistical Science and Interdisciplinary Research - Vol. 4, Advances in Multivariate Statistical Methods (A. SenGupta, Ed), World Scienti. c Press, 2009.
Brock GN, Pihur V, and Kubatko L. “Detecting gene regulatory networks from microarray data using fuzzy logic” In Fuzzy Systems in Bioinformatics, Bioengineering and Computational Biology (Studies in Fuzziness and Soft Computing) (Jin, Y. and Wang, L., Ed), Springer-Verlag, Berlin Heidelberg, 2009


External Professional Activities:
PROFESSIONAL MEMBERSHIPS AND ACTIVITIES
American Statistical Association American Society of Human Genetics International Genetic Epidemiology Society International Biometric Society
Peer Manuscript Reviewer for Bioinformatics, Information Fusion, Pattern Recognition Letters, Statistical Methodology, Communications in Statistics - Simulation and Computation, Communications in Statistics
-Theory and Methods , Statistics in Medicine, Journal of Intelligent Systems, Journal of Experimental Medicine, Disease of the Colon and Rectum, BioData Mining, BMC Medical Genetics, Computers in Biology and Medicine, BMC Bioinformatics , Computational Statistics and Data Analysis, and Brie.ngs in Bioinformatics .


Manuel Casanova, M.D.
Gottfried & Gisela Kolb Endowed Chair in Psychiatry
Associate Chair of Research
Department of Psychiatry School of Medicine
Dr. Manuel Casanova made his residency training in neurology and then spent 3 years doing a fellowship in neuropathology at The Johns Hopkins Hospital. During his stay at the Johns Hopkins Hospital, Dr. Casanova was in-charge of Pediatric Neuropathology, a fact which kindled his interest in developmental disorders of the brain. His clinical experience was enhanced by appointments as either a consultant or staff neuropathologist at Sinai Hospital (Maryland), the North Charles Hospital and the D.C. General Hospital. He spent several years as Deputy Medical Examiner for Washington, D.C., where he gained valuable experience in the post-mortem examination of Sudden Infant Death Syndrome and child abuse. His expertise in the .eld was recognized by honorary appointments as a Scienti.c Expert for the Armed Forces Institute of Pathology and as a Professorial Lecturer for the Department of Forensic Science at George Washington University. Dr. Casanova spent 8 years helping to establish 2 of the most successful brain banks in this country: The Johns Hopkins Brain Resource Center (3 years) and the Brain Bank Unit of the Clinical Brains Disorders Branch at the National Institutes of Mental Health (5 years). At present, Dr. Casanova is well published in a multitude of postmortem techniques including neuronal morphometry immunocytochemistry, neurochemistry, and autoradiography.
Dr. Casanova has had over twenty years of experience in the neurosciences. Although trained in the classical methods of neurology and neuropathology his interest has gradually shifted towards the study of abnormalities of cortical circuitry. His research has focused on the cell minicolumn, a vertical conglomerate of 80 to 100 neurons having a common latency of response to stimulation. Using computerized imaging analysis he has established the anatomical validity of the cell minicolumn. His earlier work has reported interhemispheric differences in the morphometry of minicolumns that could provide for the speciation of hominids. Localized in Broadmann area 22—part of Wernicke’s language region—the morphometric difference may play a role both in the development of language and in its disorders. His most recent studies have looked for the presence of abnormalities of minicolumnar organization and lateralization in the brains of patients who exhibit language disturbances, including autism, Asperger’s syndrome, and dyslexia. He has summarized his work on minicolumns and provided an overview of the .eld in recent reviews of the literature appearing in Brain and Brain, Behavior and Evolution.


Grants Funded:
Role: Principal Investigator Title: Building a selective inhibitory control tone in autism Funding Agency: NIH R01-MH-86784: An rTMS study Period: 2009–2013 Total Direct Costs: $888,000
Role: Principal Investigator Title: Gross morphological correlates to the minicolumnopathy of autism Funding Agency: NIH RO1 MH088893 Period: 2009-2011 Total Direct Costs: $607,859

Publications:
Seelan RS, Lakshmanan J, Casanova MF, Parthasarathy RN. Identi.cation of myo-inositol e-phosphate isoforms: characterization. Expression and putative role of a 16 kDa gamma c isoform. J Biol Chem, 284(14):9443-57, 2009.
Casanova MF, El-Baz A, Mott M, Mannheim G, Hassan H, Fahmi R, Rumsey JM, Switala AE, Farag A. Reduced gyral window and corpus callosum size in autism: possible macroscopic correlates of a minicolumnopathy. Journal of Autism and Developmental Disorders 39(5): 619-34, 2009.
Casanova MF, Trippe J, Tillquist C, Switala A. Morphometric variability of minicolumns in the striate cortex of Homo sapiens, Macaca mulatta, and Pan troglodytes. Journal of Anatomy 214(2): 226-234, 2009.
Sokhadze E, El-Baz A, Singh S, Mathai G, Sears L, Casanova MF. Effects of low frequency transcranial magnetic stimulation (rTMS) on gamma frequency oscillations and event-related potentials during processing of illusory . gures in autism. JADD 39(4): 619-634, 2009.
Sokhadze E, Baruth J, Tasman A, Sears L, Mathai G, El-Baz A, Casanova MF. Event-related potential study of novelty processing abnormalities in autism. Applied Physchophysiology and Biofeedback 34(1): 37-51, 2009.
Casanova MF, Trippe J. Radial cytoarchitecture and patterns of cortical connectivity in autism. Proceedings of the Royal Society 364: 1433-1436, 2009.
Casanova MF. La esquizofrenia como condicion neurologica debido a una falta en la lateralizacion del cerebro: observaciones micro- y macroscopicas. Revista de Neurologia, 49(3): 136-142, 2009.
Sokhadze, E., Baruth, J., El-Baz, A., Ramaswamy, R., Sears, L., Casanova, M. Transcranial magnetic stimulation study of gamma induction in response to illusory .gures in patients with autism spectrum disorders. Journal of Neurotherapy, 13(4), 271-272, 2009.
Casanova MF, El-Baz A, Giedd J, Rumsey JM, Switala A. Increased white matter gyral depth in dyslexia: implications for corticortical connectivity. Journal of Autism and Developmental Disorders 40(1): 21-29, 2009.
Casanova MF, El-Baz A, Vanbogaert E, Narahari P, Trippe J. Minicolumnar width: comparison between supragranular and infragranular layers. J Neuroscience Methods, 184(1):19-24, 2009.
Crespo FA, Fernandez-Botran R, Tillquist CR, Mott M, Casanova MF. Immune Alterations in Autism: The Role of Cytokine Polymorphisms. In Chauhan A and Brown T (eds) Autism:Oxidative Stress, In. ammation and Immune Abnormalities. Taylor and France Group, LLC, ch. 16, pp. 315-324, 2009.
Johnson SB, Casanova MF. Interhemispheric Connectivity: The Evolution and Nature of the Corpus Callosum. In TB Westland and Calton RN (eds) Handbook on White Matter: Structure, Function and Changes. Nova Science Publishers, Inc., New York, ch. 1, pp 3-15, 2009.
Casanova MF, Trippe J. Radial cytoarchitecture and patterns of connectivity in autism. F. Happe and U Frith (eds) Autism and Talent. Oxford University Press: Oxford, ch. 11, pp. 135-140, 2010.
Casanova MF, Sokhadze E, El-Baz A, Baruth J, Mathai G, Sears L. Research at the University of Louisville Autism Center. Siri K and Lyons T (eds). Cutting Edge Therapies for Autism, Skyhorse Publishing: New York, ch. 68, pp. 410-413, 2010.
Baruth J, Sokhadze E. El-Baz A, Mathai G, Sears L, Casanova MF. Transcaranial Magentic Stimulation as a Treatment for Autism. Siri K and Lyons T (eds). Cutting Edge Therapies for Autism, Skyhorse Publishing: New York, ch. 63, pp. 388-397, 2010.
Williams EL, Casanova MF. Autism and dyslexia: a spectrum of cognitive styles as de.ned by minicolumnar morphometry. Med Hyp, 74(1): 59-62, 2010.
Sokhadze E, Baruth J, Tasman A, Mansoor M, Ramswamy R, Sears L, Mathai G, El-Baz A, Casanova MF. Low frequency repetitive transcranial magnetic stimulation (rTMS) affects event-related measures of novelty processing in autism. Applied Psychophysiology and Biofeedback, 35:147-161, 2010.
Williams E, Casanova MF (2010) Potential Effects of Ultrasound on Corticogenesis: Implications for Autism. Med Hypothesis, 75:53-58, 2010.
Casanova MF, Tillquist C, Trippe J, Switala A. Radial bias in structure of dolphin insular cortex likely re.ects minicolumnar organization characteristic of mammalian neocortex. Translational Neuroscience, 1(1): 37-42, 2010.
Casanova MF. Cortical organization: a description and interpretation of anatomical .ndings based on systems theory. Translational Neuroscience, 1(1): 62-71, 2010.
Casanova MF, El-Baz A, Vanbogaert E, Narahari P, Switala A. Minicolumnar core width by lamina comparisons between autistic subjects and controls. Brain Pathology 20(2): 451-458, 2010.
Casanova MF. The pathology of paraphrenia. Current Psychiatry Reports 12(3): 196-201, 2010.
Casanova MF. The role of the entorhinal cortex in paraphrenia. Current Psychiatry Reports, 12(3): 202-207, 2010.
Sokhadze E, Baruth J, El-Baz AS, Horrell T, Sokhadze G, Carroll T, Tasman A, Sears L, Casanova M. Impaired error monitoring and correction function in autism: an ERP study. Journal of Neurotherapy, 14: 79-95, 2010.
Casanova MF, El-Baz A, Elnakib A, Giedd H, Rumsey H, Williams EL, Switala AE. Corpus callosum shape analysis by way of a pseudocylindrical map, with application to dyslexia. Translational Neuroscience, 1(2):124-130, 2010.
Baruth JM, Casanova MF, Sears L, Sokhadze E. Early-stage visual processing abnormalities in autism spectrum disorders. Translational Neuroscience, 1(2): 177-187, 2010.
Baruth JM, Casanova M, El-Baz A, Sears L, Sokhadze E. Low-frequency repetitive transcranial magnetic stimulation (rTMS) modulates evoked-gamma frequency oscillations in autism spectrum disorder (ASD). Journal of Neurotherapy, 14(3): 179-194, 2010.
El-Baz A, Elnakib A, Casanova MF, Gimel’farb G, Switala AE, Jordan D, Rainey S. Accurate automated detection of autism related corpus callosum abnormalities. Journal of Medical Systems, May 6, 2010 (Epub ahead of print).
Sokhadze E, Baruth J, Casanova MF. Neuropathological theories and EEG gamma oscillation abnormalities in autism. Neuroconnections, in press.
El-Baz A, Casanova MF, Elnakib A, Gimel’farb G, Switala AE. Image-based detection of corpus callosum variability for more accurate discrimination between dyslexic and normal brains. ISBI, in press.
Vladimir B, Jaroslav B, and Casanova MF. Plausible mechanisms for brain structural and size changes in human evolution. Collegium Anhropologicum, in press.
Elnakib A, Gimel’farb G, Casanova M, Switala A, El-Baz A. The dyslexia diagnostic by centerline-based shape analysis of the corpus callosum. 20th International Conference on Pattern Recognition (ICPR 2010), in press.
Elnakib A, El-Baz A, Casanova MF, Gimel’farb G, Switala A. Image-Based Detection of Corpus Callosum Variability for More Accurate Discrimination Between Autistic and Normal Brains, Proc. of International Conference on Medical Image Computing and Computer-Assisted Intervention (MICCAI’10), Beijing, China, September 20 - 24, 2010, vol. 1, pp. 10-18.
Farag A, Elhabian S, Abdelrahman M, Graham J, Farag A, Chen D, Casanova MF. Shape modeling of the corpus callosum. Proceedings of the 32nd Annual International IEEE EMBS, Buenos Aires, Argentina 2010. Conf Proc IEEE Eng Med Biol Soc. 2010;1:4288-91.
Williams EL, Casanova MF. Autism or Autisms? Finding the lowest common denominator. Boletin Asociacion Medica de Puerto Rico, in press.
Seelan RS, Pisano MM, Greene RM, Casanova MF, Parthasarathy R. Differential methylation of the gene encoding Myo-Inositol 3-phosphate synthase (Isyna1) in rat tissues. Epigenetics, in press.

External Professional Activities:
Editor, Autism Research Associate Editor, Translational Neuroscience Editor, Autism Insights Editor, Autism Research and Treatment Review Board, Journal of Special Education and Rehabilitation Review Editor, Frontiers in Alzheimer’s Disease
Board of Directors, Families for Effective Autism Treatment (FEAT) Advisory Board: On Mental Health (OMH) stichting, Netherlands.
06/09/2009 Center for Scienti.c Review Special Emphasis Panel ZRG1 BDCN-M - CHR
06/19/2009 Editorial Board Autism ARRA Review ZMH1 ERB-S (A1) R - (SEP)
7/20/2009 to 7/21/2009 ZRG1 BDCN-T (58) R RFA-OD-09-003 Challenge Grant
7/23/2008 to 7/25/2008
Brain Disorders and Clinical Neurosciences (BDCN) and
Molecular, Cellular and Developmental Neurosciences
(MDCN) Integrated Review Groups (IRG) Review meeting, NIH
08/2009 Marcy Speer Award Committee
10/28/2009 to 10/29/2009 2010/01 ZRG1 BBBP-R (02) M Special Emphasis Panel
02/04/2010 to 02/05/2010 Developmental Brain Disorders Study Section (TMP)


Richard D. Clover, M.D.
Dean

School of Public Health and Information Sciences

Associate Vice President for Health Affairs/Health Informatics
School of Public Health and Information Sciences
Richard D. Clover, MD is the Dean of the School of Public Health and Information Sciences and the Associate Vice President for Health Affairs/ Health Informatics. For the past several years, Dr. Clover’s research study has been focused on vaccines and informatics. With this focus in mind, Dr. Clover, along with several UL faculty members, successfully established the Center for Health Hazard Preparedness, which is based in the School of Public Health and Information Sciences. With expertise in immunizations and infectious diseases, Dr. Clover continues to be a published author in medical literature and an invited lecturer at national and international medical meetings.




Publications
Atlas RM, Clover RD, McKinney WP. “Enhancing Biosecurity Through Early Recognition and Reporting of Public Health Risks: Meeting the Challenges of the Revised International Health Regulations”. Int J Risk Assessment and Management, 2009;12:280-289.
Zimmerman RK. Middleton DB. Burns IT. Clover RD. Kimmel SR. Routine vaccines across the life span, 2007. Journal of Family Practice. 56(2 Suppl Vaccines):S18-37, C1-3, 2007 Feb.
Clover RD. Clinical practice guideline for bronchiolitis: key recommendations. American Family Physician. 75(2):171, 2007 Jan 15.

External Professional Activities
•
Member of the Institute of Medicine

•
Member of the Kentucky Institute of Medicine

•
Member of the National Board of Pubic Health Examiners

•
Member of the American Public Health Association

•
American Academy of Family Physicians Liaison Representative to the American Academy of Pediatrics, Committee on Infectious Diseases

•
Member of the Department of Health and Human Services, National Vaccine Advisory Committee

•
Chair of the American Board of Family Medicine Research and Development Committee

•
Member of the American Board of Family Medicine Examination Committee

•
Chair of the American Board of Family Medicine Information & Technology Committee

•
Health Resources and Services Administration, Peer Review Group for Faculty Development Grants

•
Member of the American Academy of Family Physicians Commission on Clinical Policies and Research Executive Committee

•
UL School of Medicine Liaison to the Louisville and Jefferson County Board of Health





Douglas Dean, Ph.D.
Gretchen and Robert Rounsavall Professor
Department of Ophthalmology James Graham Brown Cancer Center
The Rb1 pathway suppresses tumor formation by imposing cell-cell contact inhibition, which restricts tumor outgrowth, and by triggering oncogene-induced senescence, which blocks proliferation of cells with oncogenic mutations. Mutation or inactivation of this tumor suppressor pathway is a hallmark of all cancers. E-box binding transcription factors including Zeb1 regulate epithelial-mesenchymal transition (EMT), and accordingly mutation disrupts epithelial vs. mesenchymal balance in vivo. Overexpression of Zeb1 drives the EMT in cancers which is responsible an invasive metastatic phenotype and poor prognosis. Rb1 represses Zeb1, thus loss of the Rb1 pathway in cancer cells may be responsible for Zeb1 overexpression, EMT transition to invasive/metastatic disease. Beyond driving EMT, we have found that overexpression of Zeb1 is responsible for loss of Rb1 tumor suppressor functions through its repression of cyclin dependent kinase (cdk) inhibitors and miR-200. And, Zeb1 overexpresssion acts downstream of Ras mutation to cause constitutive activation of Akt and transition to invasive cancer in a mouse model.



Grants funded
Role: Principal Investigator Title: Zeb1 and epithelial-mesenchymal balance in the eye. Funding agency: NIH Direct Costs: $250,000 per year
Role: Principal Investigator Title: Regulation of epithelial-mesenchymal transition. Funding agency: NIH Direct Costs: $200,000 per year
Role: Co-Investigator Title: MerTK regulation of the PTTG and RPE phagocytosis Funding Agency: NIH Direct Costs: $250,000 per year
Role: Co-Investigator Ttile: 14-3-3s and Notch in corneal epithelium Funding agency: NIH Direct Costs: $250,000 per year

Peer-reviewed Publications (2009-2010)
Liu Y, Xin Y, Ye F, Wang W, Lu Q, Kaplan HJ, Dean DC.Taz-Tead1 Links Cell-Cell Contact to Zeb1 Expression, Proliferation and Dedifferentiation in Retinal Pigment Epithelial Cells. Invest Ophthalmol Vis Sci. 51:3372-8 (2010)
Liu Y, Dean DC. Tumor initiation via loss of cell contact inhibition versus Ras mutation: Do all roads lead to EMT? Cell Cycle 9:897-900 (2010)
Wang Y, Dean DC, Kaplan HJ. Age-related macular degeneration. Discovery Medicine 9:13-15.
El-Naggar S, Liu Y, Dean DC. Disruption of the Rb1 Pathway Leads to Overexpression of mTor, Constitutive Phosphorylation of Akt on Serine 473, and a Block in Erk Activation. Mol Cell Biol 29:5710-7 (2009)
Liu Y, Ye F, Li Q, Tamiya S, Darling D, Kaplan HJ, Dean DC. Zeb1 Represses Mitf and Regulates Pigment Synthesis, Cell Proliferation and Epithelial Morphology. 2009. Invest Ophthalmol Vis Sci. 50:5080-8 (2009)
Liu Y, Gao L, Zuba-Surma EK, Peng X, Kucia M, Ratajczak MZ, Wang W, Enzman V, Kaplan HJ, Dean DC. Mouse Neonatal Ocular Multipotential Stem-like Cells. Exp Hematol. 37:1096-107 (2009)
Liu Y, Clem B, Zuba-Surma EK, El-Naggar S, Telang S, Jenson AB, Wang Y, Shao H, Ratajczak MZ, Chesney J, Dean DC. Mouse . broblasts lacking RB1 function form spheres and undergo reprogramming to a cancer stem cell phenotype. Cell Stem Cell 4:336-47 (2009)


Paul N. Epstein, M.D.
Professor

Department of Pediatrics Department of Pharmacology & Toxicology
School of Medicine
Dr. Epstein’s primary interests are in the causes and complications of diabetes. Dr. Epstein and his research group particularly focus on the complications of diabetic cardiomyopathy and nephropathy.
Dr. Epstein lab was the .rst to demonstrate that blood glucose is maintained by a single reaction in the pancreatic beta cell. He has developed the most accurate model of diabetes for study of diabetic nephropathy in rodents. Dr. Epstein has shown that antioxidants can protect the heart from the chronic impairment produced by diabetes. Other results from his laboratory demonstrate that antioxidant protection of one type of kidney cell, the podocyte, prevents albuminuria in diabetic mice.



Grants Funded:
Title: Podocytes and Oxidative Stress in Diabetic Kidney Funding Agency: NIH/NIDDK Direct Costs Funded: $220,000 Role: Principal-Investigator
Title: Prolonged Diabetic Damage to Cardiac Mitochondria Funding Agency: NIH Direct Costs Funded: $224,000 Role: Principal-Investigator
Title: Characterization of diabetes effects on puri. ed transgenic podocytes. Funding Agency: Juvenile Diabetes Research Foundation Direct Costs Funded: $100,000 Role: Principal-Investigator


Peer-reviewed Publications:
Chen, Y. C.; Meier, R. K.; Zheng, S.; Khundmiri, S. J.; Tseng, M. T.; Lederer,
E. D.; Epstein, P. N.; Clark, B. J. Steroidogenic Acute Regulatory (StAR)­Related Lipid Transfer Domain Protein 5 (STARD5) Localization and Regulation in Renal Tubules. Am J Physiol Renal Physiol (2009).
Doser, T. A.; Turdi, S.; Thomas, D. P.; Epstein, P. N.; Li, S. Y.; Ren, J. Transgenic overexpression of aldehyde dehydrogenase-2 rescues chronic alcohol intake-induced myocardial hypertrophy and contractile dysfunction. Circulation 119:1941-1949 (2009).
Gu, H.; Zhang, Z. H.; Epstein, P. N.; Li, L.; Harden, S. W.; Wurster, R. D.; Cheng, Z. J. Impaired barore.ex control of renal sympathetic nerve activity in type 1 diabetic mice (OVE26). Neuroscience 161:78-85 (2009).
Kralik, P. M., Long, Y. Song, Y., Yang, L. Wei, H., Coventry, S., Zheng, S., Epstein, P.N. Diabetic Albuminuria is Due to a Small Fraction of Nephrons Distinguished by Albumin Stained Tubules and Glomerular Adhesions. The American journal of Pathology: vol 175, 500-509 (2009).
Powell, D. W.; Bertram, C. C.; Cummins, T. D.; Barati, M. T.; Zheng, S.; Epstein, P. N.; Klein, J. B. Renal tubulointerstitial .brosis in OVE26 type 1 diabetic mice. Nephron Exp Nephrol 111:e11-19 (2009).
Villafuerte, B. C.; Barati, M. T.; Song, Y.; Moore, J. P.; Epstein, P. N.; Portillo,
J. Transgenic expression of insulin-response element binding protein-1 in beta-cells reproduces type 2 diabetes. Endocrinology 150:2611-2617 (2009).
Xu, J.; Long, Y. S.; Gozal, D.; Epstein, P. N. Beta-cell death and proliferation after intermittent hypoxia: role of oxidative stress. Free Radic Biol Med 46:783-790 (2009).
Yang, L.; Zheng, S.; Epstein, P. N. Metallothionein over-expression in podocytes reduces adriamycin nephrotoxicity. Free Radic Res 43:174-182 (2009).
Jianxiang Xu , Yun Huang, Fenge Li , Shirong Zheng ,Paul N Epstein The FVB Mouse Genotype Confers Susceptibility to OVE26 Diabetic Albuminuria. Am J Physiol Renal Physiol (2010).

External Professional Activities:
Associate Editor Review of Diabetic Studies NIH CADO Study Section Member

Jixiang Ding, Ph.D.
Assistant Professor
Departments of Molecular, Cellular & Craniofacial Biology
School of Dentistry
The research in Dr. Ding’s laboratory is aiming to elucidate the molecular basis of congenital diseases through understanding the molecular pathways and genetic programs that control fundamental embryonic processes such as axis formation, cardiac development, craniofacial morphogenesis and patterning. On going studies address TGF-ßs and Nodal signaling pathways during holoprosencephaly (HPE) and other craniofacial malformation such as cleft palate using genetically manipulated mouse models. We have also addressed the formation of the .rst and second heart .elds and dynamic relationship between the two heart .elds during mouse cardiac morphogenesis. The results from these studies will provide signi.cant insights into the mechanisms underlying facial abnormality and congenital heart diseases, two extremely common birth defects in US and world wide.


Grants Funded:
Role: Principal Investigator Title: Mechanism of mammalian embryonic heart formation Funding Agency: KSEF Total Direct cost requested: $72,000 Period: 07/01/2010-06/30/2012
Role: Principal Investigator Title: Regulation of Nodal signaling in holoprosencephaly Funding Agency: National Institutes of Health Type: R01 Total Direct Costs: $1,125,000 Period: In no cost extension Role: Principal Investigator Title: Regulation of Nodal signaling in holoprosencephaly Funding Agency: National Institutes of Health Type: K02 career development award Total Direct Costs: $482,958 Period: ended in June 2010.

Peer Reviewed Publications:
Jin JZ, Tan M, Warner DR, Darling DS, Higashi Y, Gridley T and Ding
J. (2010) Mesenchymal cell remodeling during mouse secondary palate reorientation. Dev Dyn 239, 2110-7.

External Professional Activities:
Manuscript reviewer for Developmental Biology; Cell, Tissue & Organ; Mechanisms of Development.
A quarter of a million babies—3% of all infants born in the US each year—have some mental or physical defect that is evident at birth. Since the causes of nearly all birth defects are largely unknown, research into molecular regulatory mechanisms responsible for normal embryogenesis provides the framework for investigations into the etiology of abnormal embryonic development.
Craniofacial malformations occur with a frequency of 1 in 600 live births annually in the United States. Our previous studies have provided substantial evidence supporting the premise that various cellular signal transduction pathways interact to regulate cell proliferation and cell differentiation in embryonic craniofacial tissue. Such interactions represent the underpinnings of a complex and delicately balanced developmental system where morphogenesis and cellular differentiation of the craniofacial region are mediated by the sequential expression of molecular signals. Our studies dealing with molecular analyses of gene function in the embryo—utilizing the developing craniofacial region—are designed to provide de.nition and clari.cation of developmental signaling pathways critical for normal embryogenesis as well as identi.cation of foci for perturbation and attendant fetal abnormalities.
Current studies—selected speci.cs outlined brie. y below—are designed to identify means by which signal transduction pathways, known to be critical in development of the craniofacial region, regulate gene expression and embryonic development.
Overview of selected laboratory investigatory areas:
•
microRNAs & epigenetic regulation of craniofacial development

•
Transcriptional coactivators and craniofacial & neural tube development.

•
Transcriptional coactivators and folate-mediated development.

•
Cigarette smoke-induced intrauterine growth retardation & adverse developmental outcomes.

•
TGFß/Smad signaling mechanisms in embryonic craniofacial development.




Grants Funded:
NIH (NICHD) Research Grant, RM Greene – PI; MM Pisano –
Co-I; (R01–HD053509)
“Transcriptional Coactivators and Pregnancy Outcomes”
2008-2013; $1,321,365

NIH Research Grant, RM Greene – PI; (R01–DE018215)
“Nutritional Epigenetics and Orofacial Development”
2008-2012 – $900,000

NCRR Center for Biomedical Research Excellence, RM Greene –
PI – (P20-RR/DE17702)
“Molecular Determinants of Developmental Defects”
2002-2013; $12,072,292

Kosair Charities – Birth Defects Center Postdoctoral Fellowship,
RM Greene – PI
2009-2011; $45,000




Robert M. Greene, Ph.D.

Professor and Chair

Department of Molecular, Cellular & Craniofacial Biology
School of Dentistry


Director
Birth Defects Center

Associate
Department of Pediatrics
Distinguished University Scholar



Peer Reviewed Publications:
Warner DR, Smith HS, Webb CL, Greene RM, Pisano MM. Expression of Wnts in the developing murine secondary palate. Internat J Develop Biol 53:1105-1115 (2009). PMC2746657
Bhatacherjee V, Horn K, Singh S, Webb CL, Pisano MM, Greene, RM. CBP/p300 and associated transcriptional coactivators exhibit distinct expression patterns during murine craniofacial and neural tube development. Internat J Develop Biol 53:1097-1104 (2009). PMC2746635
Mukhopadhyay P, Rezzoug F, Webb CL, Pisano MM, Greene RM. Suppression of chondrogenesis by Id helix-loop-helix proteins in embryonic orofacial tissue. Differentiation 77:462-472 (2009). PMC2694226
Singh S, Greene RM and Pisano MM. Arsenate-induced apoptosis in murine embryonic maxillary mesenchymal cells via mitochon drial mediated oxidative injury Birth Defects Res A 88:25-34 (2010). PMC2806510
Pisano MM, Bhatacherjee V, Wong L, Henley A, Finnell R, Greene RM. Novel folate binding protein 1 interactions in embryonic orofacial tissue. Life Sci 86:275-280 (2010). PMC2819649
Warner DR, Horn K, Pisano MM, Greene RM. PRDM16/MEL1 expression in the developing mouse embryo. Acta Histochem (accepted for publication) (2010).
Horn KH, Mukhopadhyay P, Horn KH, Esposito ER, Greene RM, Pisano MM. Prenatal exposure to sidestream tobacco smoke alters gene expression in the developing murine hippocampus. Reproductive Toxicology 29:164-175 (2010). PMID: 19969065 Mukhopadhyay P, Brock G, Pihur V, Pisano MM, Greene RM. Developmental microRNA expression pro.ling of murine embryonic orofacial tissue. Birth Defects Research A 88:511-534 (2010). PMID: 20589883
Greene RM and Pisano MM. Palate Morphogenesis: Current Understanding & Future Directions Birth Defects Research
C: Embryo Today 90:133-154 (2010). PMID: 20544696
Horn K, Warner DR, Pisano MM, Greene RM. PRDM16 expression in the developing mouse embryo. Acta Histochemica, accepted for publication - (2010). PMID: 19853285
Warner D, Mukhopadhyay P, Brock G, Pihur V, Pisano, M, Greene RM. TGFß and Wnt-3a interact to induce unique gene expression pro.les in murine embryonic palate mesenchyme cells. Reproductive Toxicology, accepted for publication – (2010).

External Professional Activities:
•
Member, NIH Challenge Grants in Health and Science Research (American Recovery and Reinvestment Act of 2009) Special Emphasis Panel/Scienti.c Review Group, ZRG1 EMNR-C ,DRG, NIH, 2009.

•
Editorial Board, Orthodontics and Craniofacial Research

•
Editorial Board, Associate Editor, Birth Defects Research, Part A: Clinical and Molecular Teratology

•
Editorial Board, Risk Management and Healthcare Policy.

•
Expert Witness – Schiller Osbourn, Barnes & Maloney, 2010-2011

•
Member, Board of Directors, Spina Bi.da Association of Kentucky, Inc.

•
Scienti.c Consultant - Genetics & IVF Institute, Inc., Fairfax, VA

•
Member, Physician Champion Network in Kentucky (advocacy for birth defects surveillance), (since 1998)




Evelyne Gozal, Ph.D.
Associate Professor

Department of Pediatrics Department of Pharmacology & Toxicology
School of Medicine
Oxygen deprivation frequently occurs in cerebrovascular disorders, pulmonary diseases, sleep apnea, and nervous system injury such as stroke and brain or spinal cord traumatic injury. All these disorders are accompanied by excessive neuronal cell loss associated with sustained or intermittent restriction in oxygen supply to the neural tissue. A succession of events leads to pathological consequences, with the primary insult, followed by a secondary wave of injury mediated by various pathophysiological mechanisms, involving both necrosis and apoptosis, and expanding the primary damage. Hypoxia induces stress-related pathways promoting angiogenesis, glycolysis, growth factors signaling, genetic instability, tissue invasion, oxidative stress and apoptosis, as part of a neural tissue stress response. Astrocytes are the most abundant cell type in the CNS and are critical to the regulation of these pathways to determine neuronal fate and disease outcome. Exposure to stress induces the expression of a highly conserved family of proteins, the heat shock proteins, a universal mechanism of cellular defense in various organisms. Constitutively expressed Hsps function as molecular chaperones and participate in protein synthesis, folding, and protein transport. During cellular stress, they play a role in preventing aggregation of damaged proteins, refolding proteins, or targeting them to degradation and may also prevent apoptosis by binding pro-apoptotic proteins and inhibiting apoptosome formation and caspase activation. Alternatively, in response to increased accumulation of misfolded or ubiquitinated proteins, Hsps can induce apoptosis to remove dysfunctional cells by releasing the bound pro-apoptotic proteins. Thus, understanding the modulation of hypoxia-induced pro-and anti-apoptotic pathways in neurons, astrocytes and supporting tissue, and their modulation by stress-induced proteins may provide novel therapeutic strategies for diseases involving insuf.cient apoptosis, such as cancer and autoimmune disease or those associated with increased apoptosis such as ischemia, neurodegenerative diseases, or traumatic injury. Therapeutic strategies interfering with the signaling events triggered in response to hypoxia/ischemia may prevent delayed injury and improve recovery.



Grants Funded:
Role: Co-Investigator Title: Modulation of Neutrophil Apoptosis by Akt-Hsp27 Signalosome Funding Agency: National Institute of Allergy and Infectious Diseases Direct costs: $ 900,000


Various projects currently under investigation in our laboratory include:
•
Cellular models in intermittent and sustained hypoxia.

•
Hypoxia-induced stress response: role of heat shock proteins in the regulation of survival kinases.

•
Signal transduction pathways underlying cellular metabolism and adaptation to hypoxia/ischemia and oxidative stress.

•
The role of stress response and heat shock protein induction in the modulation of cellular survival after spinal cord injury, and prevention of secondary traumatic injury.

•
The effect of intermittent hypoxia on glutamate transport during excitotoxic injury. An organotypic slice model of stroke.




Publications:
Sedoris KC, Ovechkin AV, Gozal E, Roberts AM. Differential effects of nitric oxide synthesis on pulmonary vascular function during lung ischemia­reperfusion injury. Arch. Physiol. Biochem. 115(1):34-46, (2009).
Clark CB, Rane MJ, El-Mehdi D, Miller CJ, Sachleben Jr. LR, Gozal E. Role of oxidative stress in Geldanamycin-induced cytotoxicity and disruption of Hsp90 signaling complex Free Radicals Biol Med. 47: 1440-1449, (2009).
Machaalani R, Gozal E, Berger F, Waters KA, Dematteis M. The effect of post- mortem intervals on regional brain protein pro.les in rats using SELDI­TOF MS analysis. Neurochem. Int. 57(6): 657-661, (2010).

David W. Hein, Ph.D.
Professor and Chair
Department of Pharmacology and Toxicology School of Medicine
Molecular epidemiology of cancer susceptibility, pharmacogenetics, genomics, personalized medicine, and functional genomics. Our research in molecular epidemiology identi.es individuals genetically susceptible to the development of cancer from environmental and occupational chemicals in order to focus treatment and prevention public health strategies on those at greatest risk. Our research in pharmacogenetics/genomics and personalized medicine improves our understanding of the genetic causes for drug failure and/or drug toxicity in order to optimize clinical drug therapy for each individual patient. Our research in functional genomics improves understanding of the mechanistic and clinical consequences of genetic variation in the biotransformation of carcinogens and drugs. Additional research interests focus on enhanced training opportunities in environmental health sciences and cancer education.




Grants Funded:
Title: Pharmacogenetics of drug and carcinogen metabolism
Role in Project: Principal Investigator
Funding Agency: NIH/NCI (R01-CA034627)
Project Period: July 1, 2003 to December 1, 2010
Project Award: $1,724,900 (total)

Title: UofL Environmental Health Sciences Training Program
Role in Project: Principal Investigator
Funding Agency: NIH/NIEHS (T32- ES011564)
Project Period: July 1, 2009 to June 30, 2014
Project Award: $2,037,745 (total)

Title: Center for Environmental Genomics and Integrative Biology
PI: Kenneth Ramos (University of Louisville)
Funding Agency: NIH (P30-ES014443)
Role in Project: Center Investigator
Project Period: June 4, 2007 to March 31, 2011
Project Award: $4,440,000 (total)

Title: N-acetyltransferase 1 polymorphism and breast cancer risk
PI: Lori Millner (University of Louisville)
Role in Project: Mentor
Funding Agency: BC083107 Department of Defense Breast Cancer
Research Program
Project Period: September 29, 2008 to September 28, 2011
Project Award: $92,442 (total)

Title: Summer Environmental Health Sciences Training Program
Funding Agency: NIEHS T35- ES014559
PI: Russell A. Prough (University of Louisville)
Role in Project: Student Mentor
Project Period: April 1, 2006 to March 31, 2011
Project Award: $158,355 (total)

continue page 16 continued from page 15
Title: Understanding and predicting individual cancer risk
Role in Project: Principal Investigator
Funding Agency: UofL Clinical & Translational Science Pilot Grant Program
Project Period: June 1, 2010 to May 31, 2011
Project Award: $50,000 (total)

Title: Pharmacogenetics of drug and carcinogen metabolism
Role in Project: Principal Investigator
Funding Agency: NIH/NCI (R01-CA034627-23S1)
Project Period: July 1, 2008 to December 1, 2010
Project Award: $25,000 (total)

Title: NAT1 and NAT2 Genotype Determinations in Cancer Patients and
Controls
Funding Agency: MD Anderson Cancer Center
Role in Project: Principal Investigator
Project Period: January 1, 2004 to December 31, 2009
Project Period: $60,000 (total)

Title: NAT1 and NAT2 Metabolism Studies with Hair Dye Arylamines
Role in Project: Principal Investigator
Funding Agency: Procter and Gamble, Inc. Research Agreement #155482
Project Period: July 2, 2007 to July 1, 2009
Project Award: $100,000 (total)

Title: UofL Environmental Health Sciences Training Program
Role in Project: Principal Investigator
Funding Agency: NIH/NIEHS (T32- ES011564)
Project Period: July 1, 2004 to June 30, 2009
Project Award: $697,188 (total)

Title: Cardiovascular toxicity of environmental aldehydes
Funding Agency: NIH/NIEHS (P01- ES011860)
Role in Project: Coinvestigator on Project 1
Program PI: Aruni Bhatnagar (University of Louisville)
Project Director: Russell Prough (University of Louisville)
Project Period: July 1, 2003 to June 30, 2009
Project Period: $6,986,060 (total)

Title: A pharmacogenetic approach to prostate cancer susceptibility
PI: La Creiss Kidd (University of Louisville)
Funding Agency: NCI (R03- CA128028)
Role in Project: Co-investigator
Subproject Period: June 12, 2007 to May 31, 2009
Subproject funding: $148,000

Title: Nashville Breast Health Study
PI: Wei Zheng (Vanderbilt University)
Funding Agency: Vanderbilt University (NCI R01-CA100374 subcontract)
Role in Project: Subproject Principal Investigator
Subproject Period: May 3, 2007 to April 30, 2009
Subproject funding: $134,006

Title: Polymorphic genes of detoxi.cation enzymes as risk factors for PSP
Role in Project: Co-Principal Investigator
Funding Agency: UofL Center for Environmental Genomics and Integrative
Biology
Project Period: April 1, 2008 to June 30, 2009
Project Award: $30,000 (total)

Title: Cancer Education Grant Program
PI: Norbert J. Burzynski (University of Louisville)
Role in Project: Mentor
Funding Agency: NIH/NCI (R25- CA044789)
Project Period: August 1, 2002 to January 31, 2009
Project Award: $557,437 (total)



Publications:
Martin, R.C.G., Li, Y., Liu, Q., Jensen, N.S., Barker, D.F., Doll, M.A. and
Hein, D.W.: Manganese superoxide dismutase V16A single-nucleotide
polymorphism in the mitochondrial targeting sequence is associated with
reduced enzymatic activity in cryopreserved human hepatocytes. DNA and
Cell Biology 28: 3-7, 2009. (Epub September 26, 2008). [PMCID: 2851837]

Jefferson, F.A., Xiao, G. H., and Hein, D.W.: 4-Aminobiphenyl down
regulation of NAT2 acetylator genotype-dependent N- and O-acetylation of
aromatic and heterocyclic amine carcinogens in primary mammary epithelial
cell cultures from rapid and slow acetylator rats. Toxicological Sciences 107:
293-297, 2009. (Epub October 8, 2008). [PMCID:2605175]

Goebel, C., Hewitt, N.J., Kunze, G., Wenker, M., Hein, D.W, Beck, H., Skare,
J.: Skin metabolism of aminophenols: Human keratinocytes as a suitable
in vitro model to qualitatively predict the dermal transformation of 4-amino-2­hydroxytoluene in vivo. Toxicology and Applied Pharmacology 235: 114-123,
2009. (Epub November 28, 2008).

Zhang, Y.W., Eom, S.-Y., Kim, Y.-D., Song, Y.-J., Yun, H.-Y., Park, J.-S., Youn,
S.-J., Kim, B.S., Kim, H. and Hein, D.W.: Effects of dietary factors and the
NAT2 acetylator status on gastric cancer in Koreans. International Journal of
Cancer 125: 139-145, 2009. (Epub February 3). [PMCID: 2766547]

Turesky, R.J., Bendaly, J., Yasa, I., Doll, M.A. and Hein, D.W.: The impact of
NAT2 acetylator genotype on mutagenesis and DNA adducts from 2-amino­9H-pyrido[2,3-b]indole. Chemical Research in Toxicology 22: 726-733, 2009.
(Epub February 25). [PMCID: 2673018]

Bendaly, J., Metry, K.J., Doll, M.A., Jiang, G-H., States, J.C., Smith, N.B.,
Neale, J.R., Holloman, J.L., Pierce, W.M., and Hein, D.W.: Role of human
CYP1A1 and NAT2 in 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine­induced mutagenicity and DNA adducts. Xenobiotica 39: 399-406, 2009.
(Epub March 19). [PMCID: 2789189]

Wang, Y., Feng, W., Xue, W., Tan, Y., Hein, D.W., Li, X.-K., and Cai,
L.: Inactivation of GSK-3ß by metallothionein prevents diabetes-related
changes in cardiac energy metabolism, in.ammation, nitrosative damage
and remodeling. Diabetes 58: 1391-1402, 2009. (Epub March 26). [PMCID:
2682666]

Hein, D.W.: N-acetyltransferase SNPs: Emerging concepts serve as a
paradigm for understanding complexities of personalized medicine. Expert
Opinion on Drug Metabolism and Toxicology 5: 353-366, 2009. [PMCID:
2762189]

Blomeke, B., Brans, R., Coenraads, P.-J., Dickel, H., Bruckner, T., Hein,
D.W., Heesen, M., Merk, H.-F., and Kawakubo, Y.: Para-phenylenediamine
and allergic sensitization: risk modi.cation by N-acetyltransferase 1 and 2
genotypes. British Journal of Dermatology 161: 1130-1135, 2009.

(Epub June 11)
Metry, K.J., Neale, J.R., Bendaly, J., Smith, N.B., Pierce Jr., W. M., and Hein, D.W.: Effect of N-acetyltransferase 2 polymorphism on tumor target tissue DNA adduct levels in rapid and slow acetylator congenic rats administered 2-amino-1-methyl­6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo­[4,5-f]quinoxaline (MeIQx). Drug Metabolism and Disposition 37: 2123-2126, 2009. (Epub August 10). [PMCID: 2774981] Bendaly, J., Doll, M.A., Millner, L.M., Metry, K.J., Smith, N.B., Pierce Jr., W. M., and Hein, D.W.: Differences between human slow N-acetyltransferase 2 alleles in levels of 4-aminobiphenyl-induced DNA adducts and mutations. Mutation Research 671: 13-19, 2009. (Epub August 12). [PMCID: 2783811]


Baumgartner, K.B., Schlierf, T.J., Yang, D., Doll, M.A., and Hein, D.W.: N-acetyltransferase 2 genotype modi.cation of active cigarette smoking on breast cancer risk among Hispanic and non-Hispanic white women. Toxicological Sciences 112: 211-220, 2009. (Epub August 19). [PMCID: 2782353]
Lavender, N.A., Benford, M.L., VanCleave, T.T., Brock, G.N, Kittles, R.A., Moore, J.H., Hein, D.W. and Kidd, L.R.: Examination of polymorphic glutathione S-transferase (GST) genes, tobacco smoking and prostate cancer risk among men of African descent: A case-control study. BMC Cancer 9: 397, 2009. [PMCID: 2783040]
Kilfoy, B.A., Zheng, T., Lan, Q., Han, X., Holford, T., Hein, D.W., Qin, Q., Leaderer, B., Morton, L.M., Yeager, M., Boyle, P., Zhao, P., Chanock, S., Rothman, N., and Zhang, Y.: Genetic variation in N-acetyltransferases 1 and 2, cigarette smoking, and risk of non-Hodgkin lymphoma. Cancer Causes and Control 21: 127-133, 2010. (Epub October 7, 2009). PMCID 2972187
Hein, D.W., Millner, L.M., Leggett, C.S. and Doll, M.A.: Relationship between N-acetyltransferase 2 single nucleotide polymorphisms and phenotype. Carcinogenesis 31: 326-327, 2010. (Epub November 23, 2009). [PMCID: 2812573]
Metry, K.J., Neale, J.R., Doll, M.A., Howarth, A.L., States, J.C., McGregor,
W. G., Pierce Jr., W. M., and Hein, D.W.: Effect of rapid human N-acetyltransferase 2 haplotype on DNA damage and mutagenesis induced by 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,8­dimethylimidazo-[4,5-f]quinoxaline (MeIQx). Mutation Research 684: 66-73, 2010. (Epub December 11, 2009). [PMCID: 2820402]
Jones, A.E., Brown, K.C., Werner, R.E., Gotzkowsky, K., Gaedigk. A., Blake, M., Hein, D.W., van der Horst, C., and Kashuba, A.D.: Variability in drug metabolizing enzyme activity in HIV-infected patients. European Journal of Clinical Pharmacology 66: 475-485, 2010. (Epub January 19). [PMCID: 2855129]
Kanaan, Z., Eichenberger, M.R., Young, M., Colliver, D., Crawford, N., Cobbs, G.A., Hein, D.W. and Galandiuk, S.: An alternative cyclin-D1 splice site is not linked to in.ammatory bowel disease-associated neoplasia. International Journal of Biological Markers 25: 27-31, 2010. (PubMed) [PMCID: 2873677]
Doll, M.A., Zang, Y., Moeller, T. and Hein, D.W.: Codominant expression of N-acetylation and O-acetylation activities catalyzed by N-acetyltransferase 2 in human hepatocytes. Journal of Pharmacology and Experimental Therapeutics
334: 540-544, 2010. (Epub April 29). [PMCID: 2913773]
Martin, R.C.G., Li, Y., Liu, Q., Barker, D.F., Doll, M.A. and Hein, D.W.: Manganese superoxide dismutase expression as a function of genotype and lung cancer pathology. Cancer Investigation 28: 813-819, 2010.
Garcia-Closas, M., Hein, D.W., Silverman, D., Malats, N., Yeager, M., Jacobs, K., Doll, M.A., Figueroa, J.D., Baris, D., Schwenn, M., Kogevinas, M., Johnson, A., Chatterjee, N., Moore, L.E., Moeller, T., Real, F.X., Chanock,
S. and Rothman, N.: A single nucleotide polymorphism tags varation in the arylamine N-acetyltransferase 2 phenotype in populations of European background. Pharmacogenetics and Genomics (Epub August 25, 2010).
Kidd, L.R., Hein, D.W., Woodson, K., Taylor, P.R., Albanes, D., Virtamo, J., and Tangrea, J.A.: Lack of association of N-acetyltransferase NAT1*10 allele with prostate cancer incidence, grade, or stage among smokers in Finland. Biochemical Genetics (Epub October 8, 2010).
*Hein, D.W. and Grant, D.M: Pharmacogenetics and Pharmacogenomics (Chapter 4). In: Pharmacology and Therapeutics for Dentistry, Sixth Edition, Yagiela, J.A., Dowd, F.J., Johnson, B., Mariotti, A., and Neidle, E.A., editors, pp. 69-76, Elsevier Mosby, St. Louis, 2011. (ISBN: 978-0-323-05593-2).
*Hein, D.W., Waite, L.C. and Waddell, W.J.: Toxicology milestones at the Department of Pharmacology and Toxicology, University of Louisville. In: The Society of Toxicology: The First Fifty Years (in press).
Moore, L.E., Baris, D., Figueroa, J., Garcia-Closas, M., Karagas, M., Schwenn, M., Johnson, A., Lubin, J., Hein, D.W., Dagnall, C., Colt, J., Kida, M., Jones, M., Schned, A., Cherala, S., Chanock, S., Cantor, K., Silverman, D., and Rothman, N.: GSTM1 null and NAT2 slow acetylation genotypes, smoking intensity, and bladder cancer risk: Results from the New England bladder cancer case-control study and NAT2 meta-analysis. Carcinogenesis (Epub Oct 29, 2010.)
Zhu, Y., States, J.C., Wang, Y., and Hein, D.W.: Functional effects of genetic polymorphisms in the N-acetyltransferase 1 coding and 3’ untranslated regions. Birth Defects Research (Part A): Clinical and Molecular Teratology (in press).


External Professional Activities:
Acetylation Status and Bladder Cancer-Should NAT2 Slow Acetylators be Sub-classi.ed for Risk Assessments. Invited presentation at Symposium entitled “Occupation, Aromatic Amines, Polycyclic Aromatic Hydrocarbons and Bladder Cancer, BFGA Research Institute of Occupational Medicine, Ruhr University Bochum, Germany, November 2009.
Current Nomenclature of Human Arylamine N-Acetyltransferases. Invited presentation at Fifth International Workshop on the Arylamine N-acetyltransferases, Paris, France, September 2010.
Editorial board of Acta Pharmaceutica Sinica, Pharmacogenomics, Journal of Ovarian Research, and Human Mutation (Gene editor); World Journal of Clinical Oncology.
Served as member of NIEHS Review Committee, EHS (P1).
Reviewed grants for the Pennsylvania Department of Health (three rounds)
Chaired the Arylamine N-acetyltransferase Gene Nomenclature Committee and posting of the nomenclature.


Jeffrey C. King, M.D., FACOG
Professor and Director
Division of Maternal-Fetal Medicine Department of Obstetrics, Gynecology & Women’s Health
The Division of Maternal-Fetal Medicine provides both consultative and direct patient care for women with a wide variety of medical or surgical complications of pregnancy. Some of the conditions that might qualify a women to see a Maternal-Fetal Specialist include a prior history of preterm delivery, multifetal pregnancy (triplets or greater), pre-pregnancy diabetes (Type I or II), chronic hypertension, severe asthma, or advanced maternal age. Additionally, complications that develop during the pregnancy such as inadequate fetal growth, suspected fetal anomaly, premature rupture of the membranes, preterm labor, antepartum hemorrhage, and preeclampsia often necessitate consultation with a Maternal-Fetal Specialist.
Additionally, we provide teaching and oversight for the University of Louisville medical students and the Obstetric and Gynecologic residents-in-training.
One of our primary fetal assessment tools is ultrasound imaging of the fetus. Using ultrasound we are able to visualize (if the fetus cooperates) and evaluate the major structures within the fetus. We are able to assess the fetus for major structural abnormalities and counsel them regrading prognosis. Our research interests are varied and include vaccination protection, identi.cation of patients at risk for preterm labor, hypertension management, prenatal diagnosis, patient safety initiatives, and various maternal outcomes.


Publications:
Lang CT, King JC. Maternal mortality in the United States. Best Pract Res Clin Obstet Gynaecol. 2008 Jun; 22(3): 517-31.
Lang CT, King JC. The burden of maternal mortality and morbidity in the United States and worldwide. In Handbook of Diseases Burden and Quality of Life Measures, Prof Preedy (ed) Springer-Verlag, Berlin, Chapter 310, 2008.



Zi-Jian Lan, Ph.D.

Assistant Professor

Department of Molecular, Cellular and Craniofacial Biology School of Dentistry
My research interest is to identify novel genetic factors in male and female reproduction using combined mouse genetic, molecular and cellular techniques. Currently we are investigating the function of FGF and PI3K signaling and zinc .nger proteins in the gonad. Besides, the potential role of zinc .nger proteins in modulating the action of steroid and/or orphan nuclear receptors in the gonad and mammary gland is also being investigated.



Grants Funded:
Role: COBRE supported junior investigator Title: Molecular studies of male and female reproduction Funding Agency: National Institutes of Health/National Center for Research Resources Grant Type: Center of Biological Research Excellence (COBRE) Annul Direct Costs Funded: $157,500

Publications:
Lan ZJ, Xu X, Chung ACK, Cooney AJ. Extra-germ cell expression of mouse nuclear receptor subfamily 6, group A, member 1 (NR6A1). Biology of Repro­duction 80:905–912 (2009).
Adhikari D, Flohr G, Gorre N, Shen Y, Yang H, Lundin E, Lan ZJ, Gambello MJ, Liu K. Disruption of Tsc2 in oocytes leads to overactivation of the entire pool of primordial follicles. Molecular Human Reproduction 15:765-770 (2009).
Adhikari D, Zheng W, Shen Y, Gorre N, Hämäläinen T, Cooney AJ, Huhtaniemi I, Lan ZJ, Liu K. Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles. Human Molecular Genetics 19(3):397-410 (2010).
Zhou H, Liu L, Zhang H, Lei Z, Lan ZJ. Expression of zinc .nger protein 105 in the testis and its role in male fertility. Molecular Reproduction & Develop­ment 77:511–520 (2010).
Lei Z, Lin J, Li X, Li S, Zhou H, Araki Y, Lan ZJ. Postnatal male germ cell expression of Cre recombinase in Tex101-iCre transgenic mice. Genesis (in press) (2010).



Yongqing Liu, Ph.D.
Assistant Professor
Department of Ophthalmology and Visual Sciences
The promise of tissue regeneration to repair spinal cord injury, retinal degeneration, neural degenerative diseases including Parkinson’s and heart damage have led to experiments where stem cells have been transplanted into damaged tissues in attempts to boost regeneration. The source of these stem cells has primarily been early embryos. And, such embryonic stem cells have shown promise in some animal models. However, availability of such embryonic stem cells is limited and there are also ethical considerations regarding their use. Recent studies have found that expression of four stem cell-speci.c genes in skin cells obtained from skin biopsy is suf.cient to generate patient-speci.c induced pluripotent stem cells (iPSC) for use in transplantation for tissue regeneration. However, there remains a major technical concern with the use of these cells clinically as use of virus to express stemness genes in the patient’s cells runs a risk for introduction of cancer. Because of this, we have developed a protocol for converting differentiated somatic cells to stem-like cells by self-expression of stem cell genes through sphere formation in vitro. Our current studies are focused on developing this alternate technique for generation of iPSC for their use in clinical models.



Grants Funded
Diagram Role: COBRE Supported Junior Investigator Title: Sphere-Initiated Reprogramming to Generate Induced Pluripotent Stem Cells Funding Agency: NIH/NCRR, COBRE Direct Costs Funded: $100,000

Peer-reviewed Publications:
Liu Y, Xin Y, Ye F, Wang W, Lu Q, Kaplan HJ, Dean DC.Taz-Tead1 Links Cell-Cell Contact to Zeb1 Expression, Proliferation and Dedifferentiation in Retinal Pigment Epithelial Cells. Invest Ophthalmol Vis Sci. 51:3372-8 (2010)
Liu Y, Dean DC. Tumor initiation via loss of cell contact inhibition versus Ras mutation: Do all roads lead to EMT? Cell Cycle 9:897-900 (2010)
El-Naggar S, Liu Y, Dean DC. Disruption of the Rb1 Pathway Leads to Overexpression of mTor, Constitutive Phosphorylation of Akt on Serine 473, and a Block in Erk Activation. Mol Cell Biol 29:5710-7 (2009) Liu Y, Ye F, Li Q, Tamiya S, Darling D, Kaplan HJ, Dean DC. Zeb1 Represses Mitf and Regulates Pigment Synthesis, Cell Proliferation and Epithelial Morphology. 2009. Invest Ophthalmol Vis Sci. 50:5080-8 (2009)

Liu Y, Gao L, Zuba-Surma EK, Peng X, Kucia M, Ratajczak MZ, Wang W, Enzman V, Kaplan HJ, Dean DC. Mouse Neonatal Ocular Multipotential Stem-like Cells. Exp Hematol. 37:1096-107 (2009)
Montoya-Durango DE, Liu Y, Teneng I, Kalb.eisch T, Lacy ME, Steffen MC, Ramos KS. Epigenetic control of mammalian LINE-1 retrotransposon by retinoblastoma proteins. Mutat. Res. Fund. Mol. M. 665: 20-8 (2009)
Liu Y, Clem B, Zuba-Surma EK, El-Naggar S, Telang S, Jenson AB, Wang Y, Shao H, Ratajczak MZ, Chesney J, Dean DC. Mouse . broblasts lacking RB1 function form spheres and undergo reprogramming to a cancer stem cell phenotype. Cell Stem Cell 4:336-47 (2009)


Qingxian LU, Ph.D.
Assistant Professor
Department of Ophthalmology
and Visual Sciences

The TAM receptors are mainly expressed by dendritic cell (DC) and macrophage in the immune system and, the mice lacking TAM receptors develop systemic autoimmune diseases due to inef.cient negative control of the cytokine signaling in those cells. Take the bene.t from COBRE grant support, we tested susceptibility of the TAM triple knockout (tko) mice to the retinal speci.c autoantigen to develop experimental autoimmune uveoretinitis (EAU).
We .rst discovered that the tko mice were found to have more activated T cells, among which exhibited high sensitivity to ocular IRBP autoantigens. Immunization with a low dose of IRBP caused in.ltration of lymphocytes, including CD3-positive T cells, into the tko retina. Adoptive transfer of low dose of IRBP speci.c T cells from immunized tko mice induced in. ammation and T cell invasion in the eyes. The naïve T cell in the tko background preferentially develops into Th1 cell lineage in response to autoantigen immunization. Those Th1 determination is governed by the DC cells which express TAM receptors. The DC cells without TAM receptors over produce the Th1 signature cytokines that drive Th1 polarization. We conclude that mice without TAM receptor spontaneously develop IRBP-speci.c CD4+ T cells and, are more susceptible to retinal autoantigen immunization. This TAM knockout mouse line provides an animal model to study the APC role in development of T cell mediated uveitis.



Grants Funded:
R01-EY018830 (PI: Lu, Q), 09/30/2008-08/31/2013 6 calendar NIH/NEI direct cost $250,000.00 per year Title: MerTK regulation of the PTTG and RPE phagocytosis The goal of this project is to elucidate the molecular functions of the MerTK and its downstream targets in RPE phagocytosis.
Special Scholar Award, Research To Prevent Blindness, RPB $60,000 per year, 07/01/2010 – 06/30/2011
R01-Ey019891 (Co-PI with 10% effort, PI, Dr. Qiutang Li) 1.2 Clendar NIH/NEI direct cost $250,000.00 per year Title: Role of 14-3-3sigma in development and repair of corneal epithelium
The goal of this project is to investigate the functional role of 14-3-3sigma in regulation of Notch signaling in development and repair of corneal epithelial cells.

Publications:
(The following papers acknowledged COBRE grant supporting)
Xin Y, Lu Q, and Li Q. 14-3-3sigma controls corneal epithelial cell proliferation and differentiation through the Notch signaling pathway. Biochem Biophys Res Commun. 392(4):593-8 (2010). doi:10,1016/j.bbrc.2010.01.084; PMCID: PMC2828677.
Xin Y, Lu Q, and Li Q. 14-3-3sigma is required for Club Hair Retention. J Invest Dermatol. (2010), doi:10,1038/jid.2010.56. PMID: 20237493, PMC in progress
Lu Q, Li Q, and Lu QJ. Regulation of phagocytosis by TAM receptors and their ligands Frontier in Biology. 5(3):227-237 (2010). DOI 10.1007/s11515­010-0034-5, PMCID: PMC2971555.


Rosalie Mainous, Ph.D.
Associate Professor
School of Nursing
Dr. Rosalie Mainous is the Associate Dean for Graduate Programs and Research and oversees all graduate education including the neonatal nurse practitioner program within the School of Nursing. While facilitating the research mission in the SON, she continues an active program of research that evaluates the impact of nursing care on cerebral blood . ow, oxygenation, cerebral volume and vessel resistance in the low birth weight and very low birth weight infant. With an overarching goal of the development of a prediction model for Intraventricular Hemorrhage, her current work has been in the area of umbilical artery catheters used by nurses to draw blood and administer .uids and the alterations that follow in the cerebral tissue bed. The use of near infrared spectroscopy is the instrumentation that is central to her work. She leads interprofessional teams that are carrying out research protocols at both University of Louisville Hospital and Kosair Children’s Hospital.
Dr. Mainous was appointed a Robert Wood Johnson Foundation Nurse Executive Fellow in 2009 and is involved in work at the federal level that has implications for the national health care system and the way nursing education will evolve in the future. Dr. Mainous contributed to a landmark report published by the Institute of Medicine titled The Future of Nursing: Leading Change, Advancing Health (2010). This report was prepared by the Committee on the Robert Wood Johnson Foundation Initiative on the Future of Nursing, at the Institute of Medicine, chaired by Donna Shalala. Dr. Mainous was recognized as an outstanding alumnus from the University of Kentucky this year as part of the 50th anniversary of the College of Nursing. She serves as a liaison from the National Association of Neonatal Nurses to the American Academy of Pediatrics Committee on Fetus and Newborn and is working on a technical report related to the identi.cation and management of pain in the newborn.



Grants Funded:
Role: Principal Investigator Titile: Nursing Workforce Development Grant Health Resources and Services Administration Direct Costs Funded: $36,782
Role: Principal Investigator Funding Agency: Robert Wood Johnson Foundation Titile: Nurse Executive Fellows Program Direct Costs Funded: $35,000 plus $20,000 UofL match Role: Principal Investigator Funding Agency: Somanetics Corporation Titile: Impact of Umbilical Artery Catheters on Cerebral and Renal Tissue Oxygenation Direct Costs Funded: $98,000
Role: CO-Investigator Titile: Robert Wood Johnson Foundation Nurse Executive Fellows Alumni Grant Supporting Transition to Practice in Rural Kentucky Direct Costs Funded: $10,000

Publications:
Smith Glasgow, M.E., Niederhauser, V., Dunphy, L., & Mainous, R.O. (2010). Supporting Innovation in Nursing Education: Regulatory Issues, Journal of Nursing Regulation, 1 (3), 23-27.
Smith Glasgow, M.E., Dunphy, L.M., & Mainous, R.O. (2010). Innovative Nursing Educational Curriculum for the 21st Century. NLN Educational Perspectives, 31(6), 355-357.
Mainous RO (in press). Re.ective Response to the chapter, Enhancing the Doctoral Advanced Practice Nursing Role with re.ective practice in H.
M. Dreher & M.E. Smith Glasgow (Eds), Role Development for Doctoral Advanced Nursing Practice, Springer Publishing Company.
Glasgow MES, Dunphy LM, Mainous RO. Transformational Models of Nursing across different settings: Innovative nursing educational curriculum for the 21st century in The Future of Nursing: Leading Change, Advancing Health. Institute of Medicine, 2010.
Cunningham HR, Kennedy J, Walker K, Hart J, Hutti, M, Mainous R, Clark T, Strenecky BlJ, Coleman M, Todd DJ. Providing Health Care: Using an Interdisciplinary International Service-Learning Approach (2009). (Eds.
M. Moore & P. L. Lin). In Service Learning in Higher Education: Paradigms, Applications and Challenges. Indianapolis: University of Indianapolis Press.


External Professional Activities:
•
Editorial Boards include Neonatal Network and Advances in Neonatal Care

•
National Committee: American Academy of Pediatrics Committee on Fetus and Newborn

•
Robert Wood Johnson Executive Nurse Fellow

•
Communications Chair, Organizational Leadership Network, American Association of Colleges of Nursing

•
Numerous presentations at national, international and regional meetings

•
Grant Reviewer for HRSA





observed that the neuropeptide pituitary adenylate cyclase activating peptide (PACAP) differentially affects LH and FSH secretion and subunit gene expression in vitro. He has proposed that PACAP may be important in the normal maturation and function of the pituitary-gonadal axis. He is presently performing investigations designed to evaluate possible roles for PACAP in the development, maintenance and aging of the mammalian reproductive system.
Additional research in Dr. Moore’s laboratory is directed toward elucidating the effects of maternal offspring interaction on the onset of puberty in the male. Recent work from his laboratory has determined that manipulations of the transition from suckling to independent feeding for male rats results in differential timing of the initiation of puberty. The change in feeding behavior and/or environment is somehow translated into growth and development of the testes and increased production of the gonadotropins. Future studies are proposed to examine the in.uences of social interactions and milk borne products on the timing of puberty in the male.
During 2009-2010 Dr. Moore presented at three separate meetings, published two peer reviewed manuscripts and gave several seminars on his research interests.


Grants Funded:
Role: Principal Investigator Title: Role of PACAP in the Male Fetal Pituitary Funding Agency: NIH/NICHD Total Direct Costs Funded: $209,500: Epub 2009 Feb 12.
Moore JP, Villafuerte BC, Unick CA, and Winters SJ. Developmental Changes in Pituitary PACAP Expression during the Perinatal Period: Possible Role in Fetal Gonadotroph Regulation. Endocrinology, 2009 Oct;150(10):4802-9. Epub 2009 Jul 2

External Professional Activities:
Grant reviewer for the General Directorate for Research of the Italian Ministry of Health
Reviewer for the following peer reviewed journals:
•
Journal of Andrology

•
Journal of Ovarian Research

•
Regulatory Peptides

•
Biology of Reproduction


23



Partha Mukhopadhyay, Ph.D.
Assistant Professor
Department of Molecular, Cellular & Craniofacial Biology School of Dentistry
Dr. Mukhopadhyay’s principal research focus involves investigation of the role and interaction of various peptide growth factors and transcriptional regulators, whose collective interplay can regulate neural tube and neural crest development, orofacial ontogenesis and palatogenesis. His speci.c research interests are to examine the role of the nuclear transcriptional regulators, coactivators and corepressors in craniofacial growth and anomalies, to analyze the role of growth factors like TGFßs and BMPs in orofacial development as well as characterization of the various transcription factors and their role in normal orofacial growth. Currently, he has been using DNA microarray technology to establish comprehensive “microRNA expression pro.les” of developing murine orofacial tissue and of developing neural tube to identify important candidate microRNAs regulating palatogenesis and neural tube development, respectively. In addition, his current projects investigate: (1) BMP signaling (involving BMP receptor speci.c Smads such as Smad-1, Smad-5 and Smad-8/9) during orofacial development (2) the role of Id (inhibitor of differentiation) -1, Id-2, Id-3 and Id-4 helix-loop-helix transcription factors in orofacial ontogenesis (3) Epigenetic regulation of orofacial development (4) Epigenetics and Fetal Alcohol Syndrome and
(5) Developmental neurotoxicity of prenatal environmental tobacco smoke exposure.



Peer-reviewed Publications:
Mukhopadhyay P, Brock G, Pihur V, Webb C, Pisano MM, Greene RM. Developmental microRNA expression pro.ling of murine embryonic orofacial tissue. Birth Defects Res A: Clin Mol Teratol 88:511-534 (2010).
Warner DR, Mukhopadhyay P, Brock GN, Pihur V, Pisano MM, Greene RM (2010). TGFß-1 and Wnt-3a interact to induce unique gene expression pro.les in murine embryonic palate mesenchymal cells. Reproductive Toxicology, 2010 Oct 15. [Epub ahead of print] PMID: 20955781.


Mukhopadhyay P, Horn KH, Greene RM, Michele Pisano M. Prenatal exposure to environmental tobacco smoke alters gene expression in the developing murine hippocampus. Reprod Toxico 29:164-175 (2010).
Mukhopadhyay P, Rezzoug F, Webb CL, Pisano MM, Greene RM. Suppression of chondrogenesis by Id helix-loop-helix proteins in murine embryonic orofacial tissue. Differentiation 77: 462-472 (2009).

Grants Funded:
Role: Co-Investigator [Co-PIs: Eric Rouchka and Ted Kalb.eisch] Title: “Extension of Informatics Infrastructure to Support Translational and Basic Research” Funding Agency: Department of Energy Direct Costs Funded: $1,194,300


Steve Myers, Ph.D.
Associate Professor

Department of Pharmacology & Toxicology School of Medicine
Our research examines the development and validation of biological markers of exposure to environmental hazards, including tobacco smoke and automobile exhaust. Speci.cally, we have developed and re. ned methods of analysis and utilization of hemoglobin as a biological marker of exposure assessment in individuals exposed to environmental carcinogens. Our research efforts have also led to the application of urine as a biological sample for detection of multiple carcinogens, most notably, the environmentally related polycyclic aromatic hydrocarbons. This research has led to numerous collaborative projects in many polluted areas of the world, including the Czech Republic, and the People’s Republic of China. Over the past number of years, our research has focused on the effects of maternal smoking during pregnancy and we have applied our biomarker techniques to the development of markers of tobacco related carcinogens in both maternal and neonates, especially from mothers that smoke during pregnancy. This research has led to a better understanding of the effects of tobacco smoking on fetal growth and gestation. Further studies are currently ongoing to determine the relationships between maternal and fetal metabolism and detoxi.cation of tobacco carcinogens and the effects of pharmacogenetics of enzyme variation on adduct formation, and gestational age, and neonatal growth. In an extension of these studies, we are also developing the application of amniotic .uid as a biomarker of carcinogen exposure detected in the .rst trimester of pregnancy and we are developing assays for the detection of breast milk biomarkers that can be applied to women that are breast-feeding their neonates.
Dr. Myers has served on numerous NIH as wells as EPA internal as well as external review study sections and panels. He has presented his research extensively both Internationally and throughout the United States. He also lectures in the Pharmacology and Toxicology Medical Student and Graduate Student courses, providing lectures on gastrointestinal pharmacology, local anesthetics, and biomarkers. Dr. Myers serves also as course director and lecturer of an online Basic Pharmacology course, Neonatal Pharmacology course, and Geriatric Pharmacology course and currently represents the Department of Pharmacology and Toxicology on the University of Louisville School of Medicine Faculty Forum, and serves on the School of Medicine Admissions Committee.



Publications:
Radmacher, P. G., Looney, S. W., and Myers, S. R. Polycyclic Aromatic Hydrocarbons in Maternal and Cord Blood Plasma, Polycyclic Aromatic Compounds:Analysis, Chemistry, Metabolism, and Carcinogenicity, 30(3):113
– 129, 2010.
Myers, S.R., Wright, T., Cunningham, C., and Barnes, B. GSTM1/T1 Genotypes and Benzo(a)pyrene Hemoglobin Adducts in Maternal and Fetal Blood, Polycyclic Aromatic Compounds:Analysis, Chemistry, Metabolism, and Carcinogenicity, 30(4): 189 – 205, 2010.
Myers, S.R., Wright, T., Cunningham, C., and Barnes, B. The Relationship between Maternal and Fetal CYP1A1 Genotype in Smokers and NonSmokers to Benzo(a)pyrene Hemoglobin Adducts, Polycyclic Aromatic Compounds:Analysis, Chemistry, Metabolism, and Carcinogenicity, 30(3):165
–
187, 2010.

S.
Hunter, S. Myers, and P. Radmacher Detection of Polycyclic Aromatic Hydrocarbons (PAHs) in Human Breast Milk, Polycyclic Aromatic Compounds:Analysis, Chemistry, Metabolism, and Carcinogenicity, 30(3):153

–
164, 2010.


Gravari, E., Radmacher, P. G., Adamkin, D. H., and Myers, S. R. Amino acid pro.les in infants less than 1250 g receiving total parental nutrition. Journal of Neonatal and Perinatal Medicine, in press, 2010.

Russ Prough, Ph.D.
Professor
Department of Biochemistry & Molecular Biology School of Medicine
The research pursued in Dr. Prough’s laboratory focuses on the study of the mechanism of modulation of the enzyme activity of various drug/carcinogen metabolizing enzymes by various steroid hormones and sterols. For example, Tom Geoghegan and I are studying the effect of dehydroepiandrosterone (DHEA) and its metabolites on regulation of the cytochromes P450; DHEA and DHEA sulfate are major circulating sterols in humans and some primates (5-10 µM concentration). DHEA is also a peroxisome proliferator, but regu­lates other enzyme systems in addition to those regulated by the peroxisome proliferator activated receptor alpha (PPARa). PPAR and other members of subfamily III of the steroid hormone receptors may interact and modulate their respective action as mediators of the process of gene expression. We have noted that DHEA may alter the phosphorylation status of PPARa and other nuclear receptors by inducing protein phosphatases, speci. cally protein phosphatase 2A. This action appears to be different that the action of other peroxisome proliferating agents, and may account for the action of DHEA in inducing PPAR target genes. The molecular regulation of PP2A by sterols is understudy. Another collaborative project involves the study of aldehyde toxic­ity in cardiovascular tissues, in conjunction with Aruni Bhatnagar, Sumanth Prahbu, Sanjay Srivastava, and Stanley D’Souza. Our project studies the me­tabolism of acrolein, 4-hydroxynonenal and trans-2-hexenal in vascular tissues and how tehse agents regulate of enzyme systems in cardiovascular tissue. In addition, the effects of aldehydes on expression of those cytochromes P450 that metabolize arachidonic acid to various signaling molecules is under study to elucidate how they affect vasoactive action and proliferation and/or develop­ment of vascular smooth muscle and endothelial cells. Aldehydes serve as both substrates for some of these hemoproteins, as well as mechanism-based inactivators of CYP function. The role of aldehyde dehydrogenases and gluta­thione S-transferases in clearance of aldehydes is also under study, evaluating the various isozymes of these enzymes are regulated in mouse and human.


Publications:
Conklin DJ, Haberzettl P, Prough RA and Bhatnagar A. Glutathione S­transferase P protects against endothelial dysfunction induced by exposure to tobacco smoke. American Journal of Physiology - Heart and Circulatory Physi­ology 296:H1586-H1597 (2009). [PMID: 19270193; PMCID: PMC2685347]
Robinzon B and Prough RA. A novel NADP+-dependent dehydrogenase activity for 7a/ß and 11ß-hydroxysteroids in human liver nuclei: A third 11ß-hydroxysteroid dehydrogenase. Archives of Biochemistry & Biophysics 486:170-176 (2009). [PMID: 19416720; PMCID : PMC2742889]
Conklin DJ, Haberzettle P, Lesgards J-F, Prough RA, Srivastava S, and Bhatnagar A. Increased Sensitivity of Glutathione S-Transferase P-null Mice to Cyclophosphamide-induced Urinary Bladder Toxicity” The Journal of Phar­macology & Experimental Therapeutics 331:456-69 (2009). [PMID: 19696094; PMCID Pending]
Conklin DJ, Barski OA, Juvan P, Rezen T, Rozman D, Prough RA, Vladyk­ovskaya E, Liu SQ, Srivastava S, and Bhatnagar A. Acrolein Consumption Induces Systemic Dyslipidemia and Lipoprotein Modi. cation. Toxicology and Applied Pharmacology 243:1-12 (2010). [PMID: 20034506; PMCID Pending]
Lanceta J, Prough RA, Liang R and Wang E. Impact of MicroRNAs and Their Decanalized Expression During Aging. Special Issue entitled “Epigenetic Mechanisms of Aging and Age-related Diseases. Experimental Gerontology 45:269-278 (2010). [PMID: 20034554; PMCID Pending]
Webb SJ, Falkner KC, Geoghegan TE, and Prough RA, Convergence of Multiple Nuclear Receptors Signaling, In: Charlene A. McQueen, Comprehen­sive Toxicology, Volume 2, pp. 207–230 Oxford: Academic Press (2010).

Grants and Contracts:
Role: Project 1 Leader Grant Title: Cardiovascular Toxicity of Environmental Aldehydes Funding Agency: NIEHS Program Project Grant 1 PO1 ES11860 Total Direct Costs Funded: $822,255
Role: Co-Principal Investigator Grant Title: UofL Environmental Health Sciences Pre- and Postdoctoral Training Program Funding Agency: NIEHS Center Training Grant T32 ES11564 Total Direct Costs: $1,740,745
Role: Principal Investigator Grant Title: Summer Environmental Health Sciences Training Program, Grant T35 ES 014559 Funding Agency: HIEHS/NIH Total Direct Costs: $143,635 (Pending Renewal)
Role: Mentor Grant Title: Summer Endocrinology Research Training Program”, Grant T35 DK072923 Funding Agency: NIDDK/NIH Total Direct Costs: $143,635
Role: Director, Career Development Core Grant Title: “Center for Environmental Genomics and Integrative Biology”, 1 P30 ES014443 Funding Agency: NIEHS/NIH Total Direct Cost: $250,000
Role: Director of Project 10, Translational Technology and Resources Core Grant Title: “University of Louisville’s Clinical and Translational Science Institute” Proposal Funding Agency: NIEHS/NIH Total Direct Cost: $1,702,970 (Pending)

External Professional Activities:
President, International Society for the Study of Xenobiotics (2008-2009); Past-President (2010-2011), Panel Member, NIEHS Outstanding New Envi­ronmental Scientist Award Review Panel (2009, 2010).


Rachel Neal, Ph.D.
Assistant Professor
Dept of Environmental and Occupational Health Sciences School of Public Health and Information Sciences

My research interests lie at the interface between biochemistry and toxicology with a strong mass spectrometry analytical element. My funded research program explores the linkage between developmental cigarette smoke exposure, dysregulation of lipid metabolites, and cognitive impairment. Long term research goals include elucidation of the impact of maternal toxicant exposure on offspring health in the context of different nutritional backgrounds—speci.cally, the impact of in utero and neonatal environment on fetal health measures such as birth weight, cognitive impairment, and maturity onset obesity on varied dietary backgrounds. I am currently seeking funding and collaborations to expand my research to include developmental exposures to licit/illicit drugs (alcohol and methamphetamine) as well as environmental toxins (passive smoke exposure and Pb).



Grants Funded:
NIH R21DA027466 (R. Neal, Co-PI; M.M Pisano, Co-PI) “Developmental Cigarette Smoke Exposure: Biomarkers of Neurotoxicity” $592,000
NIH 5P30ES014443 (K. Ramos, PI) Center for Genomics and Integrative Biology Young Investigator Award to R. Neal $20,000

Publications:
Chen J, Mercer G, Roth SR, Abraham L, Lutz P, Ercal N, Neal RE. Sub-Chronic Lead Exposure Alters Kidney Proteome Pro.les. Human and Experimental Toxicology. 2010. (Accepted-In press).
Neal R, Lin C, Isom R, Vaishnav K, Zigler JS Jr. Opaci.cation of Lenses Cultured in the Presence of Pb. Molecular Vision. 2010. (Accepted-In press).


M. Michele Pisano, Ph.D.
Professor Research Director
Department of Molecular, Cellular & Laboratory of Molecular Craniofacial Biology Craniofacial Development

Professor University Scholar
Department of Pharmacology & Toxicology

Molecular, Genetic and Epigenetic Developmental Mechanisms
Birth defects and congenital developmental disabilities constitute an underappreciated global pandemic. Eight million infants are born with birth defects each year – nearly forty percent of these infants and children die before the age of 5. Despite unprecedented strides in medicine and healthcare, birth defects remain the leading worldwide cause of infant mortality and childhood morbidity. These statistics notwithstanding, public health efforts in the United States and globally have failed to categorize the prevention and treatment of birth defects as national health priorities. Even international agencies such as the World Health Organization and the United Nations have failed to evolve an appreciation for the magnitude of the human health crisis associated with birth defects and developmental disabilities. In June of 2006, the United Nations General Assembly adopted a declaration urging the nations of the world to strengthen their battle against AIDS – a disease termed by then UN Secretary-General Ko.Annan as – the “greatest challenge of our generation”. Indeed, 3 million adults and children die from AIDS annually
– a sobering statistic, but one that is exceeded by the 3.3 million infants and children who die annually from birth defects and congenital developmental disabilities. Even in the United States, a country with one of the most advanced healthcare systems in the world, a child is born with a birth defect – and two babies with low birthweight – every three minutes. Moreover, despite unprecedented intellectual and technological strides in the biomedical sciences, including sequencing of the human genome and advances in prenatal care/diagnostics, the overall incidence of birth defects and developmental disabilities is not declining and the underlying causes of nearly 70 percent of all birth defects remain unknown. In view of this, the research activities in our laboratory seek to provide a better understanding of the molecular, genetic, and epigenetic basis of normal development, as well as elucidate the genes and molecules that, when altered, result in the genesis of birth defects and infant low birthweight. Particular focus is centered on prenatal, maternal and child health issues relevant to the state of Kentucky. A combination of unique characteristics in the state, including socio-economic factors and an unusually high percentage of women who continue to smoke and drink alcohol during their pregnancy, contribute to an increased prevalence of major birth defects such as oro/facial clefting, neural tube defects, fetal alcohol- and maternal diabetes-induced embryopathies, as well as infant low birthweight and developmental disabilities.


Grants Funded:
PI: M. Michele Pisano
PI: Rachel Neal
Title: “Developmental Cigarette Smoke Exposure: Biomarkers of Neurotoxicity”
Funding Agency: NIH R21DA027466
Total Direct Costs Funded: $400,000
Project Period: 2009 - 2012

PI: M. Michele Pisano
PI: Thomas B. Knudsen
Title: “Response Signatures of Alcohol Related Birth Defects”
Funding Agency: NIH R01 AA13205
Total Direct Costs Funded: $221,582.

PI: M. Michele Pisano
PI: Thomas B. Knudsen
Title: “Perinatal Programming of Breast Cancer: Fat and Estrogens”
Funding Agency: NIH R01 ES013821
Total Direct Costs Funded: $104,000.

Subproject Director: M. Michele Pisano
PI: Robert M Greene
Title: “Molecular Determinants of Developmental Defects”
Subroject: “Pre- and Postnatal Tobacco Smoke Exposure: Effects on
Neurocognitive Development”
Funding Agency: NIH P20 RR/DE017702
Subproject Direct Costs Funded: $1,061,826.

PI: M. Michele Pisano
Title: “Developmental Neurotoxicity of Prenatal Environmental Tobacco
Smoke Exposure”
Funding Agency: University of Louisville Center for Environmental
Genomics and Integrative Biology, Kenneth Ramos, Director.
Direct Costs Funded: $30,000.

Co-I: M. Michele Pisano PI: Robert M. Greene Title: “Nutritional Epigenetics and Orofacial Development” Funding Agency: NIH R01 DE018215 Total Direct Costs Funded: $900,000.
Co-I: M. Michele Pisano PI: Robert M. Greene Title: “Transcriptional Coactivators and Pregnancy Outcomes” Funding Agency: NIH R01 HD053509 Total Direct Costs Funded: $1,321,365.

Publications:
Mukhopadhyay P., F. Rezzoug, C.L. Webb, M.M. Pisano, R.M. Greene.
Suppression of chondrogenesis by Id helix-loop-helix proteins in embryonic
orofacial tissue. Differentiation 77:462-472 (2009).

Warner D.R., H. Smith, C.L. Webb, R.M. Greene, M.M. Pisano. Expression
of Wnts in the developing murine secondary palate. International Journal of
Developmental Biology 53:1105-1115 (2009).

Bhattacherjee V, K.H. Horn, S. Singh, C.L. Webb, M.M. Pisano, R.M.
Greene. CBP/p300 and associated transcriptional coactivators exhibit distinct
expression patterns during murine craniofacial and neural tube development.
International Journal of Developmental Biology 53:1097-1104 (2009).
Singh S., C.L. Webb, R.M. Greene, M.M. Pisano. Arsenate-induced
apoptosis in murine embryonic maxillary mesenchymal cells via mitochondrial­mediated oxidative injury. Birth Defects Research - Part. A 88:25-34 (2010).

Pisano M.M., V. Bhatacherjee, L. Wong, A. Henley, R. Finnell, R.M. Greene.
Novel folate binding protein 1 interacting proteins in embryonic orofacial
tissue. Life Sciences 86:275-280 (2010).

Mukhopadhyay P., K.H. Horn, R.M. Greene, M.M. Pisano. Prenatal exposure
to environmental tobacco smoke alters gene expression in the developing
murine hippocampus. Reproductive Toxicology 29:164-175 (2010).

Horn K., D.R. Warner, M.M. Pisano, R. M. Greene. PRDM1 expression in the developing mouse embryo. Acta Histochemistry. (In Press; published online Oct. 23, 2009; doi:10.1016/j.acthis.2009.09.006) (2010).
Mukhopadhyay P., G. Brock, V. Pihur, C. Webb, M.M. Pisano, R.M. Greene. Developmental microRNA expression pro.ling of muring embryonic orofacial tissue. Birth Defects Research - Part A 88:511-534 (2010).
Greene R.M., M.M. Pisano. Palate Morphogenesis: Current Understanding and Future Directions. Birth Defects Research - Part C 90:133-154 (2010).
Lu W., Guzman A., Yang W., Chapa-Garcia C.J., Shaw G.M., Greene R.M., Pisano MM, Lammer EJ, Finnell RH Zhu H. Are genes encoding critical transcriptional activators for murine neural tube development associated with human spina bi.da? BMC Medical Genetics 11:141-147 (2010).
Warner D, P. Mukhopadhyay, P, G. Brock, V. Pihur, M.M. Pisano, R.M.Greene. TGFß and Wnt-3a interact to induce unique gene expression pro.les in murine embryonic palate mesenchyme cells. Reproductive Toxicology , in press (2010).



Matthew Qiu, Ph.D.
Professor

Department of Anatomical Sciences and Neurobiology
School of Medicine
The long-term goal of our research is to understand the molecular and genetic mechanisms that control the differentiation and regeneration of motor neurons and oligodendrocytes, and develop novel molecular strategies for stimulating the de novo regeneration of motor neurons and oligodendrocytes in the injured spinal cord. Research projects include: (1) Elucidation of the molecular pathways that regulate the early speci.cation and differentiation of glia in the developing CNS. (2) Transcriptional and posttranscriptional regulation of homeodomain factors that control the early development of motor neurons and oligodendrocyte cells. (3) Isolation and characterization of the surface receptors involved in CNS myelination. (4) Lineage-speci.c differentiation of embryonic stem cells into motor neurons and oligodendrocytes for spinal cord transplantation.



Grants Funded:
Funding Agency: NIH (1R01-NS37717-09)
Role: Principal Investigator
Title: “Molecular and genetic control of oligodendrocyte development”
35% efforts 06/01/09 - 05/30/14
Direct Costs Funded: $1, 626,157

Funding Agency: NIH (1R21-NS060033)
Role: Principal Investigator
Title: “Role of Olig3 in cerebellar and precerebellar development”
10% efforts 07/01/08 - 06/30/10
Direct Costs Funded: $354,586

Funding Agency: National Multiple Sclerosis Society (RG3275)
Role: Principal Investigator
Title: Developmental regulation of axonal myelination by Necl molecules
15% efforts 07/2009-06/2012
Direct Costs Funded: $474,019

Funding Agency: Kentucky Spinal Cord and Head Injury Trust (#3-12)
Role: PI Role of protein phosphatase D in axonal myelination.
10% effort 01/09 –01/2012
Direct Costs Funded: $299,000

Funding Agency: NIH (1R01HD053509)
Role: Co-I (PI. Robert Green)
Title: “Transcriptional Coactivators and Pregnancy Outcomes”
10% effort 07/01/08 - 06/30/13
Direct Costs Funded: $1, 503,187
Title: “Transcriptional Coactivators and Pregnancy Outcomes”


Publications:
Papers:
Li SZ, Qu YC, Liu BQ, Wang GY, Zhang Y, Ma ZF, Ma TX, Qiu M, Han RF. (2009). Synergistic effects of alpha1,2-fucosyltransferase, DAF and CD59 in suppression of xenogenic immunological responses. Xenotransplantation 16(1):27-33.
Fu H, Cai J, Clevers H, Fast E, Gray S, Greenberg R, Jain M, Ma Q, Qiu M, Rowitch D, Taylor C, and Stiles C. (2009). A genome-wide screen for spatially restricted expression patterns identi.es transcription factors that regulate glial development. J. Neurosci. 29, 11399-11408
Cai J, Zhu Q, Zheng K, Li H, Qi Y, Cao Q and Qiu M (2010). Co-localization of Nkx2.2 and Nkx6.2 homeodomain proteins in myelinating oligodendrocytes. Glia 58(4):458-68 (NIHMS#2807475)
Zheng K, Li H, Zhu Y, Zhu Q and Qiu M (2010). miRNAs are required for the developmental switch from neurogenesis to gliogenesis in the spinal cord. J. Neurosci. 30 (24):8245-50
Zhu Y, Park J., Hu X, Li H, Cao Q., Zheng K, Feng G-S and Qiu M (2010). Control of oligodendrocyte generation and proliferation by Shp2 protein tyrosine phosphatase. Glia In press
Zhang H, Tse J, Hu X, Witte M, Bernas M, Kang J, Tilahun F, Hong YK, Qiu M, Chen L. (2010). Novel discovery of LYVE-1 expression in the hyaloid vascular system. Invest. Ophthalmol. Vis. Sci. In press
Hui Zhang, Xuemei Hu, Julie Tse, Firehiwott Tilahun, M Qiu, Lu Chen. (2010). Spontaneous Lymphatic Vessel Formation and Regression in the Murine Cornea. Invest. Ophthalmol. Vis. Sci. In press

Abstracts:
Qiang Zhu, Hong Li, Yiping Zhang, Sha Mi, Michael Wegner, Christopher Shields, Mengsheng Qiu (2009). Effect of Conditional Over-expression of FL-LINGO-1 or DN- LINGO-1 on Oligodendrocyte Maturation and Myelination. The Society for Neuroscience 39th Annual Meeting, 2009
Qiang Zhu, Scott R Whittemore, Yiping Zhang, Christopher B Shields and Mengsheng Qiu (2010) Genetic fate mapping of dorsally derived oligodendrocytes in mouse spinal cord during normal development and under pathological condition. The Society for Neuroscience 40th Annual Meeting, 2010


External Professional Activity:
•
NIH Study Section NINDS-A (2009)

•
Great Britain, MRC Career Development Award (2009)

•
NIH Study Section ZRG1 MDCN-N(2) (2010)



Gerard P. Rabalais, M.D., MHA
Professor and Billy F. Andrews Endowed Chair in Pediatrics
University of Louisville School of Medicine

Chief of Staff
Kosair Children’s Hospital

President and Chairman of the Board
University Physicians Associates
Gerard Rabalais, M.D., MHA, is chair of the University of Louisville Department of Pediatrics, a department of 163 faculty, 370 staff and 95 residents and fellows.
UofL Pediatrics is home to four highly regarded research units:


Kosair Children’s Hospital Research Institute
KCHRI is a unique research unit of national and international repute. One of its stated goals is to provide an outstanding scienti.c framework that may potentially lead to innovative therapeutic approaches for diseases affecting children.
Two principal research themes constitute the core of the institute:
•
The study of the neurobiology of sleep and respiratory control

•
Investigation of the biological mechanisms underlying juvenile diabetic morbidity




Kosair Charities Pediatric Clinical Research Unit
The KCPCRU is the .rst and only inpatient Pediatric Clinical Research Unit in the Kentuckiana region and is involved in the conduct of Phase I – III clinical trials in children. The center is one of 13 Pediatric Pharmacology Research Units sponsored by the National Institute of Child Health and Human Development.
The primary goal of the KCPCRU is to develop and conduct clinical, translational and basic pediatric clinical pharmacology research in collaboration with other pediatric and medical subspecialties at the University of Louisville and other PPRU sites to close the therapeutic knowledge gap for pediatric patients.

Pediatric Clinical Trials Unit
The Pediatric Clinical Trials Unit primarily conducts industry-sponsored Phase 2 and 3 vaccine studies in both children and adults. Other studies involving pediatric outpatients are also conducted and assistance in subject recruitment is provided to the Pediatric Pharmacology Research Unit.
Through PCTU activities, patients have access to new vaccines and treatments that are not yet available to the general public. Many of the vaccines that are now used in everyday practice were studied in the PCTU in the context of multicenter trials—among these are vaccines for chickenpox, rotavirus diarrhea, meningococcal meningitis, pertussis and hepatitis A, as well as unique combination vaccines.

Child Development Unit
Two major initiatives represent the focus of the Child Development Unit: restoration and preservation of the Louisville Twin Study and participation in the National Children’s Study. Additional activities include teaching related to research methods and developmental processes and outcomes in children.
The Louisville Twin Study was once internationally recognized as one of the oldest and largest studies of child development related to twin birth status. The program was a comprehensive and longitudinal evaluation of child factors such as temperament, personality, cognitive abilities, physical growth, health status, accidental injuries, and school achievement from birth through adolescence. Preservation and restoration efforts for the twin study began in 2008 and are ongoing.
The second major initiative is the collaborative effort with the School of Public Health and Information Science to establish a Study Center for the Jefferson County location of the National Children’s Study. This initiative will examine the effects of environmental in.uences on the health and development of 100,000 children across the United States from a nationally-representative sample from 105 U.S. counties.

Clinical Care
Uof L Pediatrics’ clinical component includes 21 pediatric specialty divisions, from adolescent medicine to rheumatology. These specialists offer the full range of pediatric specialty services to children as well as conduct a variety of related clinical research projects. Unique pediatric services also include:
•
Healthy for Life! A pediatric obesity program

•
Pediatric Forensic Medicine A child abuse medical assessment, diagnosis, documentation and follow-up service

•
International Adoption Clinic

•
Developmental pediatric services at Weisskopf Child Evaluation Center such as:

-Genetic Testing and care for genetic conditions
-Fetal Alcohol Syndrome Clinic
-STAR Autism Treatment
-Feeding Disorders Program

•
Pediatric Sleep Medicine

•
Interventional Cardiology


The Pediatrics faculty clinical faculty oversee the vast majority of general and subspecialty medical care at Kosair Children’s Hospital.
UofL Pediatrics provides care to children throughout the region through its 26 satellite specialty clinics and more than one dozen tele-echo sites.
Dr. Ramos is a molecular toxicologist interested in genetic and epigenetic control of mammalian gene expression, environmental genomics and computational biology. His research focuses on the reactivation of human retro-elements by environmental injury and its connection to human disease. Under his leadership as Director of the Center for Environmental Genomics and Integrative Biology, the Bioinformatics Biostatistics & Computational Biology core has assembled a team of experts representing the . elds of life sciences, bioinformatics, computer science, mathematics, medicine and statistics that assembled the computational infrastructure required to store and query large data-sets, and to build new informatics tools.
RESEARCH INTERESTS
•
Gene-environment interactions

•
Translational medicine

•
Transcriptional and post-transcriptional control of gene expression

•
Functional genomics and bioinformatics

•
Gene-gene and gene-environment interactions

•
Cell growth, differentiation, transdifferentiation



INVITED LECTURES
2009 Society of Toxicology. “Mechanisms of epigenetic regulation of L1 elements in human and murine cells”. 2009 National Academy of Sciences. “Environmental diseases: evaluation at the molecular level”. 2009 Louisiana State University. “Epigenetic control of mammalian retrolements”. 2009 Teratology Society Annual Meeting, Modeling toxicity pathways using integrative genomics and systems biology: Focus on nephrogenesis. 2010 Society of Toxicology. “Perspectives on the evolution of cardiovascular toxicology”. 2010 Mid-West DNA Repair Meeting. “Reactivation of Mobile Genetic Elements by DNA Damaging Agents”. 2010 University of Louisville, Division of Pulmonology and Critical Care. “Stress-regulated activation of mammalian retroelements”.



Grants Funded:
•
Role: Principal Investigator

•
Title: Center for Environmental Genomics and Integrative Biology (CEGIB)


•
Funding Agency: NIH/NIEHS

•
Total Direct Costs Funded:


$3,000,000
•
Role: Principal Investigator

•
Title: Role of Retroelements in Environmental Atherogenesis


•
Funding Agency: NIH/NIEHS

•
Total Direct Costs Funded:


$1,250,000
• Role: Mentor
• Title: UofL Environmental Health Sciences Training Program
•
Funding Agency: NIH/NIEHS

•
Total Direct Costs Funded: $2,037,745


•
Role: Co-nvestigator

•
Title: Convergence of MicroRNA and p53 Signaling in Multiple Myeloma: Environmental Connections


•
Funding Agency: NIH/NCI

•
Total Direct Costs Funded: $225,000


•
Role: Co-nvestigator at 5% effort

•
Title: Protection of Ischemic Myocardium


•
Funding Agency: NIH/NHLBI

•
Total Direct Costs Funded: $8,500,000





Kenneth S. Ramos, Ph.D.
Professor, Department of Biochemistry and Molecular Biology
Director, Center for Environmental Genomics and Integrative Biology
University of Louisville Health Sciences Center School of Medicine

Publications:
Montoya-Durango, D.E, Liu, Y. Teneng I., Kalb.eisch, T., Lacy, M.E., Steffen, M.C. and Ramos, K.S. Epigenetic control of mammalian LINE-1 retrotransposon by retinoblastoma proteins. Mutation Research 665:1-2, 20­28, (2009).
Ramos, K.S., Nanez A. Genetic regulatory networks of nephrogenesis: deregulation of WT1 splicing by benzo(a)pyrene. Birth Defects Res C Embryo Today. 87:2, 192-7. (2009).
Ramos, K.S. H-RAS controls phenotypic pro.les of vascular smooth muscle cells and the pathogenesis of vascular proliferative disorders. Circ Res. 104:10, 1139-1141. (2009).
Ramos, K.S. Unraveling genetic regulatory networks of mammalian retroelements. BMC Proceedings 3:1-3. (2009).
Morris, J.P., Eltonsy, N, Ramos, K.S., Heaton, M.P. and Kalb. eisch, T.S. CGeMM Discovery Browser (http://cgemm.louisville.edu/FeatureBrowser/ main.jsp). (2009).
Ramos, K.S. and Nanez, A. Genetic regulatory networks of nephrogenesis: deregulation of WT1 splicing by benzo(a)pyrene. Birth Defects Res. Embryo Today 87:192-197. (2009).
Leikauf, G. and Ramos, K.S. Functional genomics: Uncovering cellular and subcellular mechanisms of action. In Comprehensive Toxicology, Vol. 2, 717-730, Elsevier. (2010).
Kalb. eisch, T. and Ramos, K.S. Genomics, bioinformatics and computational biology. In Comprehensive Toxicology, Vol. 2, 641-662, Elsevier. (2010).
Ramos, K.S. He, Q. and Gao, H. Technological advances and predictive assays: Introduction and overview. In Comprehensive Toxicology, Vol. 2, 623-640, Elsevier. (2010).
Ramos, K.S. and Weber, T.J. Alterations in cell signaling. Introduction and overview. In Comprehensive Toxicology, Vol. 2, 447-472, Elsevier. (2010).
Stribinskis, V. and Ramos, K. Long-interspersed nuclear elements and their role in the toxic response. In Comprehensive Toxicology, Vol. 2, 403-426Elsevier. (2010).
Ramos, K.S. and Montoya, D.E. Genetic and epigenetic determinants of susceptibility to environmental injury. Introduction and overview. In Comprehensive Toxicology, Vol. 2, 253-266, Elsevier. (2010).
Nanez, A and Ramos, K.S. Receptor Systems: Introduction and overview. In Comprehensive Toxicology, Vol. 2. 71-80, Elsevier. (2010).
Ramos, K.S. Basic principles: Overview of molecular toxicology. In Comprehensive Toxicology, Vol. 2, 1-8, Elsevier. (2010).
Ramos, K.S. Volume 2: Cellular and molecular toxicology. In Comprehensive Toxicology, Vol. 2, 1-8, Elsevier. (2010).
Montoya, D.E. and Ramos, K.S. L1 retrotransposon and retinoblastoma: Molecular linkages between epigenetics and cancer. Current Molecular Medicine. 10:511-521. (2010).
Institute of Medicine, Toxicity-Pathway-Based Risk Assessment: Preparing for Paradigm Change, National Academy Press. (2010).

External Professional Activities:
•
American Medical Association

•
Society for In Vitro Biology

•
Society of Toxicology

•
American Association for the Advancement of Science

•
American Society for Cell Biology

•
American Heart Association

•
American Society for Pharmacology and Experimental Therapeutics

•
American College of Forensic Examiners

•
North American Vascular Biology Organization

•
American Society for Biochemistry and Molecular Biology

•
Association of Medical and Graduate Departments of Biochemistry




Lonnie Sears, Ph.D.
Associate Professor
Department of Pediatrics School of Medicine
Dr. Sears is Chief Psychologist and Associate Professor of Pediatrics at the Weisskopf Child Evaluation Center. He is currently involved in research studies of the genetics and neurobiology of autism spectrum disorders as well as in medical and behavioral treatments for the disorder.



Grants Funded:
•
Role: Co-Investigator

•
Title: Building a selective inhibitory control tone in autism: An rTMS study. (Manuel Casanova, P.I.).

•
Funding Agency: National Institutes of Mental Health, 2009-2012


• Total Direct Costs Funded: $871,032

Publications:
Sokhadze E, El-Baz A, Baruth J, Mathai G, Sears L, & Casanova M. Effects of a low frequency repetitive transcranial magnetic stimulation (rTMS) on gamma frequency oscillations and event-related potentials during processing of illusory .gures in autism. Journal of Autism and Developmental Disorder 39:619-634 (2009).
Sokhadze E, Baruth,J. Tasman A, Sears L, Mathai G, El-Baz A, & Casanova
M. Event-related potential study of novelty processing abnormalities in autism. Applied Psychophysiology and Biofeedback 34: 37-51 (2010).
Sokhadze E, Baruth J, Tasman A, Sears L, El-Baz A, & Casanova M. (2009). Low-frequency repetitive transcranial magnetic stimulation (rTMS) affects event-related potential measures of novelty processing in autism. Applied Psychophysiology and Biofeedback DOI 10.1007/s10484-009-9074-5(e-pub) (2009).
Sokhadze E, Baruth J, El-Baz A, Ramaswamy R, Sears L, & Casanova,
M. Transcranial magnetic stimulation study of gamma induction in response to illusory .gures in patients with autism spectrum disorders. Journal of Neurotherapy 13:271-272 (2009).

Baruth J, Casanova M, El-Baz A, Horrell T, Mathai G, Sears L, & Sokhadze
E. (2010). Low-frequency repetitive transcranial magnetic stimulation modulates evoked-gamma frequency oscillations in autism spectrum disorder Journal of Neurotherapy 14:179-194 (2010).
Baruth J, CasanovaM, Sears L, & Sokhadze E. Early-stage visual processing abnormalities in high-functioning autism spectrum disorder (ASD), Translational Neuroscience 1:177-187 (2010).

External Professional Activities:
NIH grant reviewer, Small Business: Biobehavioral and behavioral processes across the lifespan.


Ratnam Seelan, Ph.D.
Assistant Professor
Department of Molecular,
Cellular and Craniofacial Biology,
Birth Defects Center,
School of Dentistry

Dr. Seelan’s primary research interests are in understanding the genetic basis for developmental defects such as Cleft Palate. His current research focuses on identifying epigenetically regulated genes that play critical roles in the development of the mouse secondary palate. These genes are being sought by two complementary approaches. In the .rst, DNA Methylation Arrays are being probed with genomic DNA fragments enriched for methylated CpG residues, obtained from the developing palate (spanning gestational days 12-14; GD12-14), using MeDIP (methylated DNA immunoprecipitation). In the second, CpG methylation pro.les of candidate genes, identi.ed by mRNA pro.ling analysis, are being examined during GD12-14 of palatogenesis by bisul. te modi.cation of DNA, followed by sequencing. Genes showing differential methylation in the 5’ upstream region during GD12-14, consistent with their spatio-temporal expression in the developing palate are being subjected to further analysis. Thus far, one gene – Sox4 – has been identi.ed as a critical player in murine secondary palate development, and is currently the primary focus of his research. These studies are being done in collaboration with Drs. Pisano and Greene, research faculty at the Birth Defects Center. Another ongoing project examines the role of SDF1- CXCR4 signaling in the migration of trunk neural crest cells. Functional inactivation of either gene leads to perinatal lethality in the mouse and could result in late term miscarriages in humans. These studies are currently funded by the COBRE mechanism and he continues to seek additional funding support for his varied interests. Funding from an NIH R01 grant is currently pending.



Grants Funded:
Role: Sub-project Principal Investigator
Title: Regulation of Neural Crest Cell Migration by SDF1-CXCR4 signaling.
Funding Agency: National Institutes of Health/National Center for Research
Resources; Center of Biological Research Excellence (COBRE).
Direct Costs Funded: $750,000 (2008-2013).


Publications:
Seelan RS, Lakshmanan J, Casanova MF, Parthasarathy RN. Identi.cation of Myo-Inositol 3-phosphate synthase isoforms: characterization, expression and putative role of a 16 kDa .c isoform. Journal of Biological Chemistry 284: 9443-9457 (2009).
Stagner JI, Seelan RS, Parthasarathy R, White K. Reduction of ischemic cell death in cultured islets of Langerhans by the induction of cytoglobin. Islets 1: 48-52 (2009).
Seelan RS, Warner DR, Mukhopadhyay P, Greene RM, Pisano MM. Regulation of Sox4 gene expression by DNA methylation during secondary palate development. Birth Defects Research A Clin Mol Teratol 88: 400 (2010).
Seelan RS, Pisano MM, Greene RM, Casanova MF, Parthasarathy R. Differential methylation of the gene encoding Myo-Inositol Synthase (Isyna1) in rat tissues. Epigenomics (in press).


External Professional Activities:
Ad hoc reviewer - International Journal of Gynecological Cancer, 2009; BMC Systems Biology, 2010.




importance during palate development is only now being revealed. We have performed a detailed analysis of the expression pattern of many Wnt proteins in the palates of embryonic mice and found highly speci.c and unique patterns of expression. These results form the basis of future studies to elaborate the mechanism of action of the various Wnt family members during palate development with an eye toward preventing this common birth defect.


Publications:
Warner DR, Mukhopadhyay P, Brock GN, Pihur V, Pisano MM, Greene RM. TGFß-1 and Wnt-3a interact to induce unique gene expression pro. les in murine embryonic palate mesenchymal cells. Reproductive Toxicology (2010) in press.
Jin JZ, Tan M, Warner DR, Darling DS, Higashi Y, Gridley T, Ding J. Mesenchymal cell remodeling during mouse secondary palate reorientation. Developmental Dynamics 239:2110-2117 (2010).
Horn KH, Warner DR, Pisano M, Greene RM. PRDM16 expression in the developing mouse embryo. Acta Histochemica [Epub Oct 21] (2009).
Warner DR, Smith HS, Webb CL, Greene RM, Pisano MM. Expression of Wnts in the developing murine secondary palate. International Journal of Developmental Biology. 53:1105-1112 (2009).



Title: Summer Endocrine Research Training Program.
Funding Agency: NIH T35-DK072923.
07/01/06-06/30/10
Direct Costs Funded: $263,317.



Publications:
Matsumoto A.M. Snyder PJ. Bhasin S, Martin K, Weber T, Winters SJ, Spratt D, Brentzel J, O’Dea L. Stimulation of spermatogenesis with recombinant human follicle-stimulating hormone (follitropin alfa; GONAL-f®) long term treatment in azoospermic men with hypogonadotropic hypogonadism. Fertil Steril 92:979-90, (2009).
Maudar V, Winters SJ, Villafuerte BC. Hot .ashes and fatigue relieved by Metformin. Endocrine Practice, 15:30-34 (2009) PMID: 19211394 and Sterility, 94:795-825 ( 2010) PMID: 19589523
Winters SJ, Wang C. LH, Non-SHBG Testosterone and Estradiol Levels during Testosterone Replacement of Hypogonadal Men: Further Evidence that Steroid Negative Feedback Increases as Men Grow Older. J Androl, 31:281­287 (2010). PMID: 19959827


External Professional Activities:
NIH Specialized Cooperative Centers in Reproduction and Infertility Study Section.
NICHD Special Emphasis Panel, Women’s Reproductive Health 2009
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Honors:
2009 First Place, Jewish Hospital & St. Mary’s Foundation Faculty Award in category of Most Promising Clinical Application, Research!Louisville
2009 Invited Endowed Lecture (Dr. Theodore Siegal Lecture) entitled “The Rosetta Stone for Deciphering the Genomics of Cancer,” Department of Medicine


National and International Scienti. c Committee Memberships:
2009-10 Member of International Panel to development Clinical Guidelines for Estrogen and Progestin Receptor Analyses, College of American Pathologists and the American Society of Clinical Oncology, Alexandria, VA
2009 Chair, Awards Committee, International Clinical Ligand Assay Society, Boston, MA
2009 Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), NIEHS/ NIH 2010-2011.
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C.K., Paik, S., Rhodes, A., Sasano, H., Schwartz, J.N., Sweep, F.C.G., Taube, S., Torlakovic, E.E., Valenstein, P., Viale, G., Visscher, D., Wheeler, T., Williams, R.B., Wittliff, J.L., Wolff, A.C. American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer. J. Clin. Oncol. 2010 Apr 19. [Epub ahead of print] (Unabridged Manuscript at www.ASCO.org)
Hammond, M.E.H., Hayes, D.F., Dowsett, M., Allred, D.C., Hagerty, K.L., Badve, S., Fitzgibbons, P.L., Francis, G., Goldstein, N.S., Hayes, M., Hicks, D.G., Lester, S., Love, R., Mangu, P.B., McShane, L., Miller, K., Osborne, C.K., Paik, S., Rhodes, A., Sasano, H., Schwartz, J.N., Sweep, F.C.G., Taube, S., Torlakovic, E.E., Valenstein, P., Viale, G., Visscher, D., Wheeler, T., Williams, R.B., Wittliff, J.L., Wolff, A.C. American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer. Arch. Pathol. Lab. Med. 134 (6): E1-E16, 2010.
Kidd, L.C.R., Brock, G.N., VanCleave, T.T., Benford, M.L., Lavender, N.A., Kruer, T.L., and Wittliff, J.L. Angiogenesis-associated Sequence Variants Relative to Breast Cancer Recurrence and Survival, Cancer Causes and Control, 21:1545-1557, 2010 (DOI 10.1007/s10552-010-9583-9).
Wittliff, J.L., Laser Capture Microdissection and Its Use in Genomics & Proteomics, in Reliable Lab Solutions: Techniques in Confocal Microscopy (P. Michael Conn, Ed.), Elsevier Press, Boston, Chapter 29, pp. 463-477, 2010.



Kruer TL, Wittliff JL. Expression of Novel Estrogen-Response-Element Binding in Human Breast Carcinoma Predicts Clinical Behavior. San Antonio Breast Cancer Symposium, San Antonio, TX, December 2009.
Wittliff JL, Andres SA, Kerr DA. Molecular Diagnostics for Identifying an Increased Likelihood of Recurrence of Breast Cancer. Experimental Biology 2009, New Orleans, LA, 4/20-4/23/09.
Wittliff JL, Kerr II DA, Brooks M, Krissinger D, Landers M, Adams C. Distinct MicroRNA Expression Pro.les Are Associated with Sex Hormone Receptor Status of Breast Carcinoma and Menopausal State. Endocrine Society, P3­68, Washington, D.C., 6/12/09.
Wittliff JL, Andres SA, Kerr, DA. Molecular Diagnostics Identifying a Increased Likelihood of Breast Cancer Recurrence. American Association for Clinical Chemistry, Bethesda, MD, 11/5-6/09.
Wittliff JL, Andres SA, Kerr, DA.. Molecular Diagnostics Identifying an Increased Likelihood of Breast Cancer Recurrence. Research!Louisville 2009, F-33, 10/15/09.
Kruer TL, Wittliff JL. Characterization of Estrogen Response Element Binding Proteins that Predict Clinical Behavior of Human Breast Cancer. University of Louisville Biochemistry & Molecular Biology 2009 Colloquium, #7, Louisville, KY, 8/21/09.
Andres SA, Kerr DA, Englert DF, Wilson DJ., Wittliff JL. Expression of Small Sets of Genes in Carcinoma and Stromal Cells Predict Clinical Behavior of Human Breast Cancer. University of Louisville Biochemistry & Molecular Biology 2009 Colloquium, #17, Louisville, KY, 8/21/09.


Grants Funded:
Research Support Ongoing Research Support
Role: Co-investigator: Paul N. Epstein, PI with James L. Wittliff and others Funding Agency: National Institutes of Health (1 R01 DK072032-01) 02/01/05-07/31/10 Direct Costs Funded: $96,728 Title: Podocytes and Oxidative Stress in Diabetic Kidney The major goal of this project is study a speci.c aspect of nephropathy in mice, that of reactive oxygen species and their effects on podocyte biology and behavior.
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Role: Co-investigator: Douglas S. Darling, PI with James L. Wittliff and others Funding Agency: National Institutes of Health (1R01DE019243-01) 09/16/08-05/31/2013 Direct Costs Funded: $259,784 Title: Mathematical Model of Parotid Acinar Differentiation The major goal of this project is to use microarrays to generate mathematical and statistical models of parotid acinar cell terminal differentiation.
Role: Mentor Traci L. Kruer, PI with James L. Wittliff, Mentor Funding Agency: Department of Defense (CDMRP-BC083139) Pre-doctoral Award 10/01/08-09/30/11 Direct Costs Funded: $96,837 Title: Functional Characterization on an ERE-Binding Protein as a Clinically Relevant Biomarker of Breast Cancer Behavior The major goal is to link genomic and proteomic information with patient characteristics, tumor pathology/biomarker status and clinical outcome in breast cancer. Role: Mentor
Role: PI & Mentor for Sarah A. Andres Funding Agency: Phi Beta Psi Charity Trust, James L. Wittliff, PI 08/01/08-07/31/10 Direct Costs Funded: $55,350 Title: A Novel Gene Subset for Predicting Breast Cancer Recurrence & Survival The principal goal is to validate gene subsets from carcinoma and stromal cells and correlate gene expression with clinical outcome.
Role: Principal Investigator Funding Agency: Clinical and Translational Science Pilot Grant Program Basic Award, Commonwealth of Kentucky
04/15/10-04/14/11 Direct Costs Funded: $46,418 Title: Development of a Diagnostic Assay for Predicting Recurrence and Survival of Breast Cancer using an Estrogen Response Element Binding Protein The principal goal is develop standardized reagents and quality control materials for an ERE-binding protein assay that produces results predicting breast cancer behavior. Role: PI
Role: Principal Investigator Funding Agency: Clinical and Translational Science Pilot Grant Program Basic Award, Commonwealth of Kentucky 06/01/10-05/31/11 Direct Costs Funded: $48,760 Title: A Novel Molecular Diagnostic Identifying an Increased Likelihood for
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Breast Cancer Recurrence & Survival The principal goal is to validate and format the expression pro.le of a small set of genes which collectively predict the risk of recurrent breast cancer.
Role: Principal Investigator Funding Agency: Clinical and Translational Science Pilot Grant Program Basic Award, Commonwealth of Kentucky 07/01/10-06/30/11 Direct Costs Funded: $43,161 Title: Combination Diagnostic Test for Simultaneous Assessment of Risk of Breast Cancer Recurrence and Response to Hormone Therapy The principal goal is to validate the expression pro.le of a set of estrogen receptor associated genes, which collectively predict the risk of recurrent breast cancer and response to hormone therapy, and format the gene expression pro.les into a reproducible assay. Role: PI



Major Seminars:
Presidential Guest Speaker: “International Scholars Program: Gateways to Career Alternatives for Foreign Professionals”. Bosnian-Herzegovinian-American Academy of Arts and Sciences, Louisville, KY, November 7, 2009.
Invited Keynote Speaker for Evening Gala of Symposium entitled “New Developments & Trends in the Fields of IVF & Stem Cell Research, Bregenz, Austria, November 14, 2009 (Dr. Wittliff also wrote the Laudatio for Professor Herbert Zech.)
Invited Lecture entitled “Genomics and Proteomics- Based Diagnostics in Cancer: Expectations and Realities.” Aushon Biosystems, Billerica, MA, 3/23/09
Invited Lecture entitled “State of the Art Lectures Oncology: Predicting Breast Cancer Behavior using Genomic Approaches and Laser Capture Microdissection.” The Medical University of Vienna, September 9, 2009
Invited Lecture entitled “Distinct MicroRNA Expression Pro. les are Associated with Sex Hormone Receptor Status of Breast Carcinomas and Menopausal State.” Medical University of Vienna, Department of Obstetrics & Gynecology, September 2009
Invited Lecture entitled “Predicting Breast Cancer Behavior using Genomic Approaches and Laser Capture Microdissection.” Medical University of Vienna, Department of Obstetrics & Gynecology, September 2009
Invited Lecture entitled “The Rosetta Stone for Deciphering the Molecular Basis of Breast Cancer Behavior,” Institute of Applied Microbiology (BOKU), Vienna, Austria, September 8, 2009
Invited Lecture entitled “Contemporary Reproductive Biology: Molecular Approaches & Gene Expression Signatures for Predicting Clinical Behavior,” Institute for Reproductive Medicine & Endocrinology, Bregenz, Austria, September 4, 2009



Doug Darling
Professor
Department of Periodontics Endodontics and Dental Hygene School of Dentistry


Ron Gregg
Chairperson and Professor
Department of Biochemistry and Molecular Biology School of Medicine


Joseph Hersh
Professor
Department of Pediatrics Child Education Center


Tom Knudsen
Professor
Department of Molecular, Cellular and Craniofacial Biology School of Dentistry US Environmental Protection Agency



Carolyn Mervis

Professor
Department Psychology and Brain Sciences School of A&S

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