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BirthDefects2008AnnualReport.txt

Birth Defects Research:
Diagnosis; Treatment; Prevention

Those of us lucky enough to call ourselves developmental biologists
have, for the past several decades, had front row seats at one of
the most fascinating plays ever seen…a play entitled ”Embryonic
Development.” Intense scientific inquiry into molecular and cellular
processes during development has revealed secrets long hidden by
the developing embryo, transforming the field of developmental biology
from a descriptive into a predictive science. Embryogenesis is no longer
an arcane process. We are witnessing a play wherein genes, molecules
and proteins are the actors, interacting—in ways that we increasingly
understand—to create, by the final scene, a healthy baby.
Imagine each member of the audience of this play being shown the
sequence of their own genome. They would see a line of A’s, T’s,
G’s, and C’s three billion letters in length. The letters, represent the
structural units of DNA used to spell out the genetic instructions used
in development, each unique sequence defining who we are. A printed
version of this personal “Book of Life,” using the font size you see here,
would be over 30,000 pages long. Astonishingly, this is packaged into
a single cell, and using only 25,000 or so genes, this blueprint is used
to construct a human being. Yet despite the immense complexity
involved, most babies that are born are normal and healthy! One
cannot help but be amazed at Nature’s handiwork!
The more that is revealed about our
individual Book of Life, the more amazing
the story becomes. Since the unveiling
of the human genome in 2001, we have
moved from asking what in our DNA
makes us human to striving to know what
in one’s DNA makes individuals unique.
Indeed, recognition of the extent of
human genetic variation was considered
the 2007 “Breakthrough of the Year”
by Science magazine. There are over
15 million locations, known as “singlenucleotide
polymorphisms” (SNPs), in
our genomes where a single base can
differ from one person or population to
the next. A catalog of common genetic
variants that occur in human beings,
called the HapMap, describes these
variants and the location where they
occur in our DNA. This information is
being used by researchers to link genetic
variants to the risk for specific diseases
and should prove invaluable for defining risk factors for certain birth
defects.
Another form of genetic variation occurs when differences in the
number of copies of a particular region in the genome appear. Such
changes can result in an altered number of copies of a gene or piece
of regulatory DNA. Such “copy number variants,” as they are called,
have been associated with susceptibility or resistance to disease. Copy
number variants also appear to pose a risk to the developing fetus
since such variants have been associated with autism1,2, and idiopathic
learning disability3.
Despite these astounding advances in our knowledge, birth defects
continue to affect about one in every 33 babies born in the United
States each year, and are the leading cause of infant mortality. Each
year, over 3 million children die before the age of five as a result of
complications due to congenital anomalies4. Nearly twenty five percent
of all infant deaths in Kentucky are caused by congenital anomalies…
one of the highest rates in the nation. Indeed, more babies die because
of complications due to birth defects than from all other causes.
Despite ongoing research, the causes of nearly 70% of birth
defects remain unknown! Nevertheless, significant advances have
been achieved in our understanding of the causes and risk factors
associated with congenital anomalies. For example, we now know
that: obesity confers a higher risk of serious birth defects of the brain
and spine; dietary supplementation with folic acid lowers the risk of
having a baby with a neural tube defect; exposure to cigarette smoke
increases the risk of giving birth to a low birth weight baby or one with
a cleft palate; Accutane™, a drug used to treat severe acne, during
pregnancy causes severe birth defects; and consumption of alcohol
(wine, beer, or liquor) is the leading known preventable cause of mental
and physical birth defects.
“In a scientific experiment, there are two possible outcomes: If the result
confirms the hypothesis, then you’ve made a measurement. If the result is
contrary to the hypothesis, then you’ve made a discovery”
—Enrico Fermi (1901-1953)
2
Message from the Director
1Science 316:445 (2007)
2Psychiatr Genet. 18:101-109 (2008)
3The Lancet 354: 1676 (1999)
4 March of Dimes, 2006
The critical challenge for the Birth Defects Center at the University of
Louisville’s to improve the diagnosis and treatment of birth defects as
well as effect their prevention. To address this mission, investigators in
the Birth Defects Center are engaged in the conduct of fundamental
research on molecular and molecular genetic aspects of embryonic
development and congenital malformations. In the pages that follow,
it can be seen that the Birth Defects Center seeks to 1) examine how
genes and the environment work together to cause birth defects, 2)
enable prenatal molecular diagnosis of maternal genetic susceptibility
to potential fetal hazards such as exposure to tobacco, alcohol and
certain medications, and 3) define the etiology of developmental
abnormalities such as autism, neural tube defects, orofacial clefting,
holoprosencephaly, diabetic embryopathy, learning and cognitive
disorders, and idiopathic infertility as well as others.
While many examples of individual research support can be
acknowledged (see individual faculty profiles 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 significant support
from Kosair Charities. On belhalf 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 5 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 5 years in the amount of $8.8 million.
It is our hope that research activities conducted by members of the
Birth Defects Center will result in a tangible improvement in our ability to
diagnosis birth defects as well as lead to intervention strategies resulting
in the reduction of the frequency of birth defects. For those of you that
read on—once again, enjoy the journey!
Robert M. Greene, Ph.D.
3
“The great tragedy of science — the slaying of a
beautiful hypothesis by an ugly fact”
—TH Huxley (1825-1895)
Adamkin DH. Controversies in Neonatal
Nutrition: Docosahexanoic Acid (DHA) and
Nucleotides. J Perinatol 27:S79-82 (2007).
Bhatia J, Young TE, Adamkin DH. Discussion 4:
Nutritional Update. J Perinatol 27:S83 (2007).
Adamkin DH. Early Aggressive Nutrition: Parenteral Amino Acids and
Minimal Enteral Nutrition for Extremely Low Birthweight <1000g Infants.
Edizioni Minerva Medica S.P.A. 59:369-377 (2007).
Batton DG, Adamkin DH, Bell EF, Denson SE, Engle WA, Martin GI,
Stark AR. Barrington KJ, Raju T N.K., Riley LR, Tomashek KM, Wallman
C, Couto J. Co-Bedding Twins and Higher-Order Multiples in a Hospital
Setting. Pediatrics 120:1359-1366 (2007).
Adamkin DH. Use of Intravenous Lipids in
Very Low Birthweight Infants. NeoReviews
8(12): e543-e546 (2007).
Engle WA, Tomashek KM, Wallman C,
Adamkin DH, Barrington KJ, Batton DG, Bell
EF, Couto J, Denson SE, Martin GI, Stark AR,
Raju T N.K., Riley LR. Late- Preterm Infants: A
Population at Risk. Pediatrics 120:1390-1401
(2007).
Adamkin DH. Nutritional Rehabilitation for Brain Injured Infants:
Catch-Up Growth is Good! Invited commentary, Pediatrics, 121(1):181-
182 (2008).
Engle WA, Blackmon LR, Stark AR, Adamkin DH (COFN), Batton, DG,
Bell EF, Denson SE, Martin GI, Bhutani VK. Surfactant-Replacement
Therapy in the Neonate. Pediatrics 121(2):419-432 (2008).
Abbasi SA, Stewart DL, Radmacher PG, Adamkin DH. Natural Course
of Cholestasis in Neonates on Extracorporeal Membrane Oxygenation
(ECMO): 10 Year Experience at a Single Institution. ASAIO J 54 (4):
436-438, (2008).
Committee on the Fetus and Newborn, American Academy of
Pediatrics, Post-discharge follow up of infants with congenital
diaphragmatic hernia. Pediatrics 121(3):627-632 (2008).
Research Activities:
David Adamkin, MD, serves as Director of the Division of Neonatal
Medicine and the Neonatal Nutrition Research Lab with 15 faculty and 7
neonatal fellows. Additionally, he is a member of the Committee on the
Fetus and Newborn of the American Academy of Pediatrics. In 2007
and 2008, he gave 88 scientific presentations in the USA, Canada and
Poland as well as serving as a visiting professor in the United States
and Poland. Recent research has focused on growth strategies in
preterm infants both during hospitalization and after discharge. He has
produced 11 peer reviewed publications, 2 book chapters, 6 books/
educational videos in the years 2007-08.
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: Lactoferrin enhances growth and reduces nosocomial infection
in preterm infants
Funding Agency: Agennix
Direct Costs Funded: $86,363
Peer-reviewed Publications:
Batton DG, Adamkin DH, Bell EF, Denson SE, Engle WA, Martin GI,
Stark AR. Barrington KJ, Raju T N.K., Riley LR, Tomashek KM, Wallman
C, Couto J. Non-initiation or Withdrawal of Intensive Care for High-Risk
Newborns. Pediatrics 119:401-403 (2007).
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David Adamkin, M.D.
Professor
Department of Pediatrics
Director
Division of Neonatal Medicine
Director
Neonatal Fellowship Program
Director
Nursery at Norton’s Hospital
Director
Neonatal Nutrition Research
Program
Associate Professor of Obstetrics
School of Medicine
Research Activities
Dr. Brock’s research interests include statistical genetics and the
analysis of microarray data. He is also interested in developing
methods for handling proteomic data.
Grants Funded
Role: Statistical Core
Title: Molecular Determinants of Developmental Defects
Funding Agency: NIH/NCRR
Direct Costs Funded: $297,367 (core only)
Role: Statistical Consultant
Title: Center for Environmental Genomics and Integrative Biology
Bioinformatics, Biostatistics and Computational Biology Core
Funding Agency: NIH/NIEHS
Direct Costs Funded: $600,000 (core only)
Role: Co-Investigator
Title: Transcriptional Coactivators and Pregnancy Outcomes
Funding Agency: NIH
Direct Costs Funded: $255,546
Role: Co-Investigator
Title: Nutritional Epigenetics and Orofacial
Development
Funding Agency: NIH
Direct Costs Funded: $250,000
Role: Co-Investigator,
Biostatistician
Title: A Pharmacogenetic
Approach to Prostate Cancer
Susceptibility
Funding Agency: National
Cancer Institute, NIH
Direct Costs Funded: $50,000
Peer-reviewed Publications
Brock, G., Weeks, D.E., Sobel, E. and Feingold, E. (2007) “A novel
method for estimating significance levels in NPL scores for large
pedigrees” Genet Epidemiol., 31(5):417-430.
Brock, G., Shaffer, J.R., Blakesley-Ball, R.E., Lotz, M.J., and Tseng,
G.C. (2008) “Which missing value imputation method to use in
Guy Brock
Assistant Professor
Department of Bioinformatics
School of Public Health &
Information Sciences
expression profiles: a comparative study and two selection schemes”
BMC Bioinformatics 9(1):12
Bordon, J., Peyrani, P., Brock, G., Blassi, F., Rello, J., File, T., Ramirez,
J.A., and the CAPO Study Group. “The care of hospitalized patients
with community-acquired pneumonia should not be altered by the
presence of pneumococcal bacteremia: Results from the communityacquired
pneumonia organization (CAPO) international cohort study.”
CHEST, 2008. 133(3):618-24
Pihur, V., Brock, G., Datta, S. and Datta, S. “Cluster validation for
microarray data: An appraisal”. In Indian Statistical Institute Platinum
Jubilee Series (A. SenGupta, Ed), World Scientific Press, to appear
(2008).
Bhattacharjee, S., Kuo, C-L., Mukhopadhyay, N., Brock, G., Weeks,
D.E., and Feingold, F. (2008) “Robust score statistics for QTL linkage
analysis” The American Journal of Human Genetics 82(3):567-82.
Brock, G., Pihur, V., Datta, S., and Datta, S. (2008) “clValid, an R
package for cluster validation” Journal of Statistical Software Vol. 25,
Issue 4, Mar 2008.
Brock, G., Beavis, W., and Salter, L. (2008) “Fuzzy and related
methods as screening tools fordetecting gene regulatory Networks,”
Information Fusion (in press).
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Research Activities
The neural development requires both genetic (intrinsic) and
environmental (extrinsic) factors at different embryonic and postnatal
stages. Either lack is destined for CNS dysplasia. Our general
research goal is to understand molecular pathways and genetic
programs that control the CNS development. Currently it focuses
on transcriptional regulation on the generation, specification and
differentiation of both neuronal and glial cells, which is a pivotal
intrinsic mechanism to control neural cell fate. In addition, we are
also interested in how environmental factors affect this process. The
study aims: (1) to identify and characterize candidate genes that
are specifically expressed in neurons or glias; (2) to investigate the
‘molecular switches’ in CNS that are involved in hypoxia, aging, or
developmental and neurological disorders such as attention-deficit
hyperactivity disorder (ADHD), autism, multiple sclerosis (MS),
amyotrophic lateral sclerosis (ALS) etc; (3) to develop molecular
and/or cellular strategies for preventive or therapeutic purpose.
The experimental approaches cover molecular cloning, RNA in situ
hybridization, immunohistochemistry, Western blot, gene targeting,
in ovo electroporation, and in vitro explant or stem cell culture. The
electrophysiological and neurobehavioral assessments are also
performed for functional analyses. Ongoing projects include:
• PAF signaling in normal CNS development.
• Oligodendroglial injury and sleep apnea-associated intermittent
hypoxia.
Grants Funded
Role: Principal Investigator
Title: Oligodendrocyte Generation in Prenatal Exposure to
Intermittent Hypoxia
Funding Agency: University of Louisville
Direct Costs Funded: $4,942
Jun Cai, M.D., Ph.D.
Assistant Professor
Department of Pediatrics
School of Medicine
Role: COBRE Supported Junior Investigator
Title: Intermittent Hypoxia-mediated Oligodendrocytes Defects in a
Murine Model of Gestational Sleep Apnea
Funding Agency: NIH/NCRR, COBRE
Direct Costs Funded: $50,000
Role: Principal Investigator
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
Peer-reviewed Publications
Liu Z, Hu X, Cai J, Liu B, Peng X, Wegner M, Qiu, M. Induction
of oligodendrocyte differentiation by Olig2 and Sox10: evidence
for reciprocal interactions and dosage-dependent mechanisms.
Developmental Biology 302: 683-693 (2007)
Zhang YP, Shields LB, Pei J, Zhang Y, Xu XM, Hoskins R, Cai J,
Qiu MS, Magnuson DS, Burke DA, Shields CB. Use of magnetic
stimulation to elicit motor evoked potentials, somatosensory evoked
potentials, and H-reflexes in non-sedated rodents. Journal of
Neuroscience Methods 165(1): 9-17 (2007).
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Hoffman W, Casanova MF, Cudrici CD, Zakranskaia E, Venugopalan
R, Nag S, Oglesbee MJ, Rus H,. Neuroinflammatory response of the
choroids plexus epithelium in fatal diabetic ketoacidosis. Experimental
and Molecular Pathology 83(1):65-72, 2007.
El-Baz A, Casanova MF, Gimel’farb G, Mott M, Switala A. A New
Image Analysis Approach for Automatic Classification of Autistic Brains.
Proc.of IEEE International Symposium on Biomedical Imaging: From
Nano to Macro (ISBI’07), Arlington, Virginia, USA, April 12–15, 2007,
pp. 352-355.
Fahami R, Casanova MF, Farag A: Robust neuroimaging-based
classification techniques of autistic vs. typically developing brain, In:
Biomedical imaging: From nano to macro. Piscataway, NJ: IEEE; 352-
355, 2007.
El-Baz A, Casanova MF, Gimel’farb G, Mott M, Switala A. Autism
Diagnostics by 3D Texture Analysis of Cerebral White Matter
Gyrifications. Proc. of International Conference on Medical Image
Computing and Computer-Assisted Intervention (MICCAI’07), 10(Pt. 2):
882-890, 2007.
Casanova MF, Switala AE, Trippe J, Fitzgerald M. Comparative
minicolumnar morphometry of three distinguished scientists. Autism
11(6):557-569, 2007.
Casanova MF. Schizophrenia as a deficit in the modulation of cortical
minicolumns by monoaminergic systems. International Review of
Psychiatry 19(4): 361-372, 2007.
Fahmi R, El-Baz A, Hassan H, Farag A, Casanova MF. Classification
Techniques for Autistic Vs. Typically Developing Brain Using MRI Data,
Proc. of IEEE International Symposium on Biomedical Imaging: From
Nano to Macro (ISBI’07), Arlington, Virginia, USA, April 12–15, 2007,
pp. 1348-1351.
Abd EL Munim H, Farag AA, Casanova MF, Frequency-Domain
Analysis of the Human Brain for Studies of Autism, Proceedings, 7th
IEEE International Symposium on Signal Processing and Information
Technology, ISSPIT 2007, Cairo, Egypt, December 15-18, 2007, pp.
1198-1203.
Casanova MF, Kreczmanski P, Trippe J, Switala A, Heinsen H,
Steinbusch HWM. Schmitz S. Neuronal distribution in the neocortex of
schizophrenic patients. Psy Res 158(3):266-277, 2008.
Research Activities
The focus of the laboratory is the study of cortical circuitry abnormalities
in psychiatric conditions. Previous work established: 1) the validity
of the cell minicolumn as a template for cortical organization and, 2)
how interhemispheric differences in the morphometry of minicolumns
provided for the speciation of hominds. More 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.
Grants Funded
Role: Principal Investigator
Title: Modular Abnormalities of Brain Organization in Autism
Funding Agency: National Institutes of Health
Direct Costs Funded: $540,000
Role: Co-Investigator
Title: Mood Stabilizing Medications and the Inositol Signaling System
Funding Agency: Department of Veterans Affairs—VA Merit Review
Direct Costs Funded: $1,044,200
Peer-reviewed Publications
Casanova MF, Switala A, Trippe J. A comparison study on the vertical
bias in neocortex and hippocampus. Developmental Neuroscience,
29(1-2):193-200, 2007.
Casanova MF, Trippe J, Switala AE: A temporal continuity to the
vertical organization of the human neocortex: a study spanning prenatal
development and aging. Cerebral Cortex, 17(1):130-137, 2007.
Gottfried & Gisela Kolb Endowed Chair
in Psychiatry
Associate Chair of Research
Department of Psychiatry
School of Medicine
Manuel Casanova, M.D.
Casanova MF. The minicolumnopathy of autism: a link between
migraine and gastrointestinal symptoms. Medical Hypothesis, 70:73-
80, 2008.
Casanova MF, Tillquist C. Encephalization, emergent properties, and
psychiatry: a minicolumnar perspective. The Neuroscientist, 14:101-
118, 2008.
Seelan RS, Khalyfa A, Lakshmanan J, Casanova MF, Parthasarathy
RN. Deciphering the lithium transcriptome: microarray profiling
of lithium modulated gene expression in human neuronal cells.
Neuroscience, 151(4): 1184-1197, 2008.
Casanova MF, Konkachbaev AI, Switala AE, Elmaghraby AD.
Recursive trace line method for detecting myelinated bundles: a
comparison study with pyramidal cell arrays. Journal of Neuroscience
Methods, 168(2):367-372, 2008.
Fajardo C, Escobar MI, Buritca E, Artega G, Umbarilla H, Casanova
MF, Pimienta H. Von Economo neurons are present in the dorsolateral
(dysgranular) prefrontal cortex of humans. Neuroscience Letters
435(3):215-218, 2008.
El-Zehiry N, Casanova MF, Elmaghraby A. Variability of the relative
corpus callosum cross sectional area between dyslexic and normally
developed brains. International Symposium of Biomedical Engineering
(ISBI), in press.
El-Baz A, Casanova MF, Gime’farb G, Mott M, Switala, VanBogaert
E, McCracken R. Dyslexia diagnostic by 3D Texture analysis of cerebral
white matter gyrifications. IEEE International Conference on Image
Processing (San Diego, California), in press.
El-Baz A, Casanova MF, Gime’farb G, Mott M, Switala. An MRI-based
diagnostic framework for early diagnosis of dyslexia. International
Journal of Computer Assisted Radiology and Surgery, in press.
automatic orientation.png: A 35 µm thick section through human cortex
(Brodmann area 22) is shown, spanning a region 4.5 mm by 2.7 mm in
size. Arrows represent the local radial direction r' computed automatically
using the Fourier transform to detect anisotropy. The routine fails in lamina I,
where there is no columnar structure present in a Nissl stain, but otherwise
performs adequately.
El-Zehiry N, Casanova MF, Elmaghraby AS. Analyzing the
Development and the Functionality of Dyslexic and Autistic Brains
by Investigating the Relationship between the Microstructures and
Macrostructures. MICCAI 2008 Workshop on Imaging the Early
Developing Brain: Challenges and Potential Impact, in press.
Casanova MF, El-Baz A, Mott M, Mannheim G, Hassan H, Fahmi
R, Rumsey JM, Switala AE, Farag A. Reduced gyral window and
corpus callosm size in autism: possible macroscopic correlates of a
minicolumnopathy. Journal of Autism and Developmental Disorders, in
press.
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, in press.
Sokhadze E, El-Baz A, Singh S, Mathai G, Sears L, Casanova MF.
Evoked and induced gamma frequency oscillations, interhemispheral
coherence and event-related potential abnomarlities during processing
of illusory figures in autism spectrum disorders. JADD in press.
Chance SA, Casanova MF, Switala AE, Crow TJ. A post-mortem
study of reduced surface area asymmetry and altered minicolumn
spacing in planum temporale in schizophrenia and review of MRI
findings. Brain, in press.
8
“Tough Guy”
9
Research Activities
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.
Peer-reviewed Publications
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.
Richard D. Clover, Ph.D.
Research Activities
We are studying the molecular basis for trafficking of secreted
proteins within the cell during regulated secretion. Secretory proteins
synthesized in the major salivary glands, including the parotid glands,
are primarily stored in dense-core secretory granules and released
in response to external stimuli (regulated or stimulated secretion).
Parotid salivary proteins are secreted apically, primarily by the regulated
secretory pathway. Understanding how sorting occurs in salivary glands
would contribute to the correct targeting of therapeutic transgenes. To
study the molecular basis for trafficking, we use a proteomics approach
to define proteins in the secretory granule membrane, and systems
biology approaches to define regulatory pathways. We hope to define
the developmental mechanisms that create the secretory pathways.
In addition, our laboratory is interested in the regulation of gene
transcription in eucaryotic cells. We are investigating the molecular
mechanism of action of the zfh family of transcription factors. We
have isolated cDNA and genomic clones of the Zfhep/Zfhx1a/
ZEB1 transcription factor. ZEB1 is essential for life as well as T-cell
development, craniofacial development, and skeletal patterning. ZEB1
is a SMAD-binding protein, and therefore is part of the TGFbeta family
signaling mechanism. Current projects investigate the role of ZEB1 and
related genes in early development, and the molecular interactions that
underlie those roles. We focus on development of the eye, which has
specific defects in ZEB1-mutant mice that mimic birth defects in some
human babies. In addition, we are studying the molecular basis for cleft
palate in ZEB1 knock-out mice.
Grants Funded
Role: Principal Investigator
Title: Selective Aggregation and Sorting of Salivary Protein
Funding Agency: National Institutes of Health, NIDCR
Direct Costs Funded: $875,000
Role: Principal Investigator
Title: Ocular Defects Caused by TCF8/Zfhx1a Mutation
Funding Agency: NIH/ NEI
Direct Costs Funded: $275,000
Role: Co-Investigator
Title: Oral H. pylori Prevalence in Intellectually/Developmentally
Disabled Adults
Funding Agency: NIH/NIDCR
Direct Costs Funded: $275,000
Douglas Darling, Ph.D.
Dean
School of Public Health and
Information Sciences
Associate Vice President for Health
Affairs/Health Informatics
School of Public Health and
Information Sciences
Professor
Department of Periodontics,
Endodontics & Dental Hygiene
School of Dentistry
Role: Principal Investigator
Title: Identifying Periodontal Antigens By Protein Microarray
Funding Agency: NIH/NIDCR
Direct Costs Funded: $275,000
Role: Co-Investigator; PI Ken Ramos
Title: Center for Environmental Genomics and
Integrative Biology (CEGIB)
Funding Agency: NIH/NIEHS
Direct Costs Funded: $3,000,000
Role: Principal Investigator
Title: Mathematical Model of Parotid Acinar Differentiation
Funding Agency: NIH/NIDCR
Direct Costs Funded: $1,900,000
Peer-reviewed Publications
S.G. Venkatesh, J. Tan, S.U. Gorr and D.S. Darling (2007)
Isoproterenol Increases Sorting Of Parotid Gland Cargo Proteins To
The Basolateral Pathway. Am J Physiol Cell Physiol. 293: C558 - C565.
PMID: 17537806, PMCID: PMC2084485.
Manavella PA, Roqueiro G, Darling DS, and Cabanillas AM. (2007)
The ZFHX1A gene is differentially autoregulated by its isoforms.
Biochem. Biophys. Res. Commun. 360(3): 621-626. PMID:17610840.
doi:10.1016/j.bbrc.2007.06.088
Kitchens DH, Binkley CJ, Wallace DL, Darling DS, (2007) Helicobacter
pylori Infection in Intellectually and Developmentally Disabled Persons:
A Review. Special Care in Dentistry. 27 (4):127-33, PMID:17972442.
Liu Y, Costantino ME, Durango-Montoya D, Darling DS, and Dean
DC (2007): The zinc finger transcription factor ZFHX1A is linked to cell
proliferation through the Rb/E2F pathway. Biochem. J. 408(1): 79-85.
doi:10.1042/BJ20070344. PMID:17655524. PMCID: PMC2049079.
Kowase T, Walsh HE, Darling DS, and Shupnik MA (2007) Estrogen
Enhances GnRH-Stimulated Transcription of the LH Subunit Promoters
via Altered Expression of Stimulatory and Suppressive Transcription
Factors. Endocrinology, 148: 6083 – 6091. doi;10.1210/en.2007-
0407. PMID:17823254.
Liu Y, El-Naggar S, Darling DS, Higashi Y, and Dean DC (2008)
Zeb1 links epithelial-mesenchymal transition and cellular senescence.
Development 135, 579-588. doi:10.1242/10.1242/dev.007047.
PMID: 18192284.
Jin JZ, Li Q, Higashi Y, Darling DS, and Ding J (2008) Analysis of
Zfhx1a mutant mice reveals palatal shelf contact-independent medial
edge epithelial differentiation during palate fusion. Cell and Tissue
Research, 333:29-38. doi: 10.1007/s00441-008-0612-x
Singh M, Spoelstra NS, Jean A, Howe E, Torkko KC, Clark HR, Darling
DS, Shroyer KR, Horwitz KB, Broaddus RR, and Richer JK (2008)
ZEB1 expression in type I vs type II endometrial cancers: a marker of
aggressive disease. Mod Pathol. 21(7): 912-23. PMID 18487993.
Liu Y, Peng X, Tan J, Darling DS, Kaplan HJ, and Dean DC (2008)
Zeb1 Mutant Mice as a Model of Posterior Corneal Dystrophy. Invest.
Ophthalmol. Vis. Sci., 49: 1843 - 1849. DOI: 10.1167/iovs.07-0789.
10
11
Research Activities
My research interests include Bioinformatics, Biostatistics, Statistical
issues in Population Biology, Statistical Genetics, Infectious Disease
Modeling and Survival Analysis. My latest interest is in stochastic
modeling of biological systems. In bioinformatics my research
includes transcriptomics (microarray data analysis),
proteomics (analysis of MALDI-MS, MALDI-MS/MS, SELDI
data) and metabolomics. I have generated my own data
to detect biomarker of fetal alcohol related disorder.
In a nutshell, my research involves high dimensional
data analysis using modern multivariate clustering
and classification techniques. I am involved in
collaborative research with interdisciplinary scientists
from Biochemistry, Biology, Public Health and Computer
scientists. My research is funded by National Science Foundation and
National Institute of Health.
Grants Funded
Role: Principal Investigator
Title: Statistical Peak Detection, Adaptive Classification and Protein-
Protein Network Construction Using Mass Spectra
Funding Agency: National Science Foundation-Division of
Mathematical Sciences
Direct Costs Funded: $150,000
Role: Co-Investigator
Title: Center for Environmental Genomics and Integrative Biology
Funding Agency: NIH/NIEHS
Direct Costs Funded: $3,000,000
Susmita Datta, Ph.D.
Role: Co-Investigator
Title: Pediatric Clinical Proteomics Center
Bioinformatics data analysis for multiple
proteomics project for pediatric
proteomic clinical data.
Funding Agency: NIH/NIDDK
Direct Costs Funded: $3,000,000
Role: Co-Investigator
Title: Urinary Proteomics in Aminoglycoside-
Treated Newborns
Funding Agency: NICHD
Direct Costs Funded: $125,000
Role: Principal Investigator Subcontract
Title: Assessment of Pathway Design through Multi-level Modeling
and Experimentation
Funding Agency: National Science Foundation
Direct Costs Funded: $692,460
Peer-reviewed Publications
Datta, S., Le-Rademacher, J. and Datta, S. (2007). Predicting patient
survival from microarray data by accelerated failure time modeling using
partial least squares and LASSO, Biometrics, 63, 259-271.
Datta, S., Datta, S., Parrish, R. S. and Thompson, C. M. (2007).
Microarray data analysis. In Computational Methods in Biomedical
Research, R. Khatree and D. Naik, eds., Chapman & Hall/CRC
Biostatistics Series, Volume 24, 1-43.
Boratyn, G. M., Datta, S. and Datta, S. (2007). Incorporation of
biological knowledge into distance for clustering genes. Bioinformation,
1, 396-405.
Pihur, V., Datta, S. and Datta, S. (2007). Weighted rank aggregation of
cluster validation measures: A Monte Carlo cross-entropy approach.
Bioinformatics, 23, 1607-1615.
Pihur, V., Datta, S. and Datta, S. (2008). Finding cancer genes through
meta-analysis of microarray experiments: Rank aggregation via
the cross entropy algorithm. Genomics, to appear. doi:10.1016/j.
ygeno.2008.05.003
Associate Professor
Department of Bioinformatics and
Biostatistics
School of Public Health and
Information Sciences
12
Pihur, V., Datta, S. and Datta, S. (2007). Understanding Chronic
Fatigue Syndrome (CFS) from CAMDA data: A systems biology
approach. Proceedings of CAMDA 2007, full paper, online @
http://camda.bioinfo.cipf.es/camda07/agenda/detailed.html.
Pihur, V., Brock, G., Datta, S. and Datta, S. (2008). Cluster validation
for microarray data: An appraisal. In Multivariate Statistical Methods,
( A. SenGupta, ed), ISI Platinum Jubilee series, Vol 5, World Scientific
Press, to appear (2008).
Brock, G., Pihur, V., Datta, S. and Datta, S. (2008). clValid , an R
package for cluster validation. Journal of Statistical Software, 25, 4.
Pihur, V., Datta, S. and Datta, S. (2008). Reconstruction of genetic
association networks from microarray data: A partial least squares
approach. Bioinformatics, 24, 561-568.
Datta, S., Turner, D., Singh, R., Ruset, B., Pierce, W. M., and
Knudsen, T. B. (2008). Fetal alcohol syndrome in mice detected
through proteomics screening of the amniotic fluid. Birth Defects
Research Part A: Clinical and Molecular Teratology, 82, 177-186.
Datta, S. and Pihur, V. (2008). Feature selection and machine
learning with mass spectrometry data, R. Matthiesen, ed., In Clinical
Proteomics: Methods, Applications and Tools, Humana Press, to
appear.
Research Activities
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,
neural induction and placenta formation. 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 first and second heart fields and dynamic relationship
between the two heart fields during mouse cardiac morphogenesis. In
addition to the mouse genetic approach, we have also established the
Zebrafish model system in the laboratory aiming to dissect the details
of the pathways controlling the above developmental processes.
Grants Funded
Role: Principal Investigator
Title: Regulation of Nodal signaling in holoprosencephaly
Funding Agency: National Institutes of Health
Direct Costs Funded: $1,125,000
Role: Principal Investigator
Title: Regulation of Nodal signaling in holoprosencephaly
Funding Agency: National Institutes of Health
Direct Costs Funded: $482,958
Peer-reviewed Publications
Jin JZ, Li Q, Higashi Y, Darling DS, Ding J. Analysis of Zfhx1a mutant
mice reveals palatal shelf contact-independent medial edge epithelial
differentiation during palate fusion. Cell Tissue Res. 33: 29-38 (2008)
Jixiang Ding, Ph.D.
Assistant Professor
Departments of Molecular, Cellular &
Craniofacial Biology
School of Dentistry
E#2: double in situ hybridization
of the Mlc2a gene (red) and
the Cripto gene (brown) in wild
type embryo showing that Cripto
expression is located within the
developing heart region
Research Activities:
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. They also
investigate the loss of beta cell function that occurs with autoimmune
reactions and disrupted sleep cycles.
Dr. Epstein was the first 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.
He has also demonstrated that a specific cardiac metabolite controls
cardiac insulin sensitivity. Other results from his laboratory demonstrate
that antioxidant protection of one type of kidney cell, the podocyte,
prevents albuminuria in diabetic
Grants Funded:
Role: Principal Investigator
Title: Podocytes and Oxidative Stress in Diabetic Kidney
Funding Agency: NIH/NIDDK
Direct Costs Funded: $250,000
Role: Principal-Investigator
Title: Prolonged Diabetic Damage to Cardiac Mitochondria
Funding Agency: NIH
Direct Costs Funded: $244,000
Role: Principal-Investigator
Title: Podocyte Specific Antioxidant Protection in Diabetic Nephropathy
Funding Agency: Juvenile Diabetes Research Foundation
Direct Costs Funded: $60,000
Role: Principal-Investigator
Title: Antioxidant Transgenes In Diabetic Cardiomyopathy
Funding Agency: NIH/NHLBI
Direct Costs Funded: $200,000
Role: Principal-Investigator
Title: Altered Glucose Homeostasis by Sleep Impairment
Funding Agency: NIH/NHLBI
Direct Costs Funded: $225,000
Professor
Department of Pediatrics
Department of Pharmacology &
Toxicology
School of Medicine
13
Role: Collaborator
Title: B-cells in Pups of Mild and Severe
STZ Diabetic Mothers; Antioxidant Protection
Funding Agency: NIH
Direct Costs Funded: $200,000
Role: Collaborator
Title: Training Program in Transplantation
Funding Agency: NIH/NHLBI
Direct Costs Funded: $823,577
Role: Collaborator
Title: UofL Environmental Health Sciences Training Program
Funding Agency: NIH/NIEHS
Peer-reviewed Publications:
Ai, J.; Epstein, P. N.; Gozal, D.; Yang, B.; Wurster, R.; Cheng, Z.
J. Morphology and topography of nucleus ambiguus projections to
cardiac ganglia in rats and mice. Neuroscience 149:845-860; 2007.
Paul N. Epstein, M.D.
14
Donthi, R. V.; Epstein, P. N. Altering and analyzing glucose metabolism
in perfused hearts of transgenic mice. Methods Mol Med 139:151-161;
2007.
Han, J.; Xu, J.; Long, Y. S.; Epstein, P. N.; Liu, Y. Q. Rat maternal
diabetes impairs pancreatic beta-cell function in the offspring. Am J
Physiol Endocrinol Metab 293:E228-236; 2007.
Song, Y.; Du, Y.; Prabhu, S. D.; Epstein, P. N. Diabetic
Cardiomyopathy in OVE26 Mice Shows Mitochondrial ROS Production
and Divergence Between In Vivo and In Vitro Contractility. Rev.Diabet.
Stud. 4:159-168; 2007.
Zaruba, R. A.; Epstein, P. N.; Carr, P. A. Hyperglycemia alters enzyme
activity and cell number in spinal sensory ganglia. J Brachial.Plex.
Peripher.Nerve Inj. 2:11; 2007.
Gu, H.; Epstein, P. N.; Li, L.; Wurster, R. D.; Cheng, Z. J. Functional
changes in baroreceptor afferent, central and efferent components of
the baroreflex circuitry in type 1 diabetic mice (OVE26). Neuroscience
152:741-752; 2008.
Teiken, J. M.; Audettey, J. L.; Laturnus, D. I.; Zheng, S.; Epstein, P. N.;
Carlson, E. C. Podocyte loss in aging OVE26 diabetic mice. Anat Rec
(Hoboken) 291:114-121; 2008.
Wang, Q.; Donthi, R. V.; Wang, J.; Lange, A. J.; Watson, L. J.; Jones,
S. P.; Epstein, P. N. Cardiac phosphatase-deficient 6-phosphofructo-
2-kinase/fructose-2,6-bisphosphatase increases glycolysis,
hypertrophy, and myocyte resistance to hypoxia. Am J Physiol Heart
Circ Physiol 294:H2889-2897; 2008.
Xu, J.; Han, J.; Long, Y. S.; Epstein, P. N.; Liu, Y. Q. The role of
pyruvate carboxylase in insulin secretion and proliferation in rat
pancreatic beta cells. Diabetologia 51:2022-2030; 2008.
Xu, J.; Han, J.; Long, Y. S.; Lock, J.; Weir, G. C.; Epstein, P. N.; Liu,
Y. Q. Malic enzyme is present in mouse islets and modulates insulin
secretion. Diabetologia; 51:2281-2289; 2008.
Zheng, S.; Carlson, E. C.; Yang, L.; Kralik, P. M.; Huang, Y.; Epstein, P.
N. Podocyte-Specific Overexpression of the Antioxidant Metallothionein
Reduces Diabetic Nephropathy. J Am Soc Nephrol; 19:2077-2085;
2008.
Yang, L.; Zheng, S.; Epstein, P. N. Metallothionein over-expression in
podocytes reduces adriamycin nephrotoxicity. Free Radical Research;
2008 In Press.
David W. Powell, Clinton C Bertram, Timothy D. Cummins, Michelle
T. Barati, Shirong Zheng, Paul N. Epstein and Jon B. Klein: Renal
Tubulointerstiti al Fibrosis in OVE26 Type 1 Diabetes Mice. In Press
2008.
Jianxing Xu, Yun-Shi Long, David Gozal and Paul N. Epstein Beta Cell
Death and Proliferation after Intermittent Hypoxia: Role of Oxidative
Stress . Free Radical Biol Med In Press 2008.
Research Activities
Dr. Gozal’s research interests include bench to bedside approaches
to the study of pediatric sleep disorders and respiratory control
using sophisticated techniques such as gene arrays and protein chip
technologies, and also more specific studies on cellular and animal
models of sleep-disordered breathing. In addition, Dr. Gozal’s research
program conducts clinical, physiological, and epidemiological studies
on sleep in children.
Grants Funded
Role: Principal Investigator
Title: Neurocognitive Function in Snoring Children
Funding Agency: National Heart Lung and Blood Institute
Direct Costs Funded: $1,500,000
Role: Principal Investigator, University of Louisville Site
Title: Tonsillectomy and Adenoidectomy in Children with Sleep
Disordered Breathing
Funding Agency: National Heart Lung and Blood Institute, Multi-
Center Study
Direct Costs Funded: $200,000 (UofL site)
Role: Co-Investigator
Title: Sleep and Sleep Disorders In ChildrenFunding Agency: NIH,
National Heart Lung and Blood Institute
Direct Costs Funded: $1,250,000
Role: Principal Investigator
Title: Oxidative Stress in a Murine Model of Sleep Apnea
Funding Agency: National Heart Lung and Blood Institute
Direct Costs Funded: $1,250,000
David Gozal
Peer-reviewed Publications
O’Brien LM, Gozal D. Potential usefulness of non-invasive autonomic
monitoring in recognition of arousals in normal healthy children. J. Clin.
Sleep. Med. 2007; 3:41-47.
Montgomery-Downs HE, Gozal D. Toddler behavior after
polysomnography: effects of unintended partial sleep deprivation. Sleep
2006; 29:1282-1287.
Molfese V, Beswick J, Molnar A, Jacobi-Vessels J, Gozal D. The
impacts of sleep duration, problem behaviors and health status on letter
knowledge in pre-kindergarten children. Child Health and Education: An
Interdisciplinary Journal. 2007; 1:41-53.
O’Brien LM, Holbrook CR, Jones VF, Gozal D. Ethnic differences in
periodic leg movements in children. Sleep Med 2007;8:240-246.
Tauman R, Serpero LD, Sans Capdevila O, O’Brien LM, Goldbart
AD, Kheirandish-Gozal L, Gozal D. Adipokines in children with sleepdisordered
breathing. Sleep 2007; 30:443-449.
Tauman R, O’Brien LM, Gozal D. Hypoxemia and obesity modulate
plasma C-reactive protein and interleukin 6 levels in snoring children.
Sleep & Breathing 2007; 11;77-84.
Professor
Department of Pediatrics
School of Medicine
Director
Kosair Children’s Hospital Research
Institute
Distinguished University Scholar
Mediano O, Barcelo A, de la Pena M, Gozal D, Agusti A, Barbe F.
Sleepiness and polysomnographic variables in sleep apnea patients. Eur.
J. Resp. Med. 2007; 30:1396-1399.
De la Pena Bravo M, Serpero LD, Barcelo A, Barbe F, Agusti A, Gozal
D. Inflammatory proteins in patients with obstructive sleep apnea with
and without daytime sleepiness. Sleep & Breathing 2007; 11:177-185.
Dayyat E, Maarafeya MAM, Sans Capdevila O, Kheirandish-Gozal L,
Montgomery-Downs HE, Gozal D. Nocturnal body position in sleeping
children with and without obstructive sleep apnea. Pediatr. Pulmonol.
2007; 42:374-379.
Kheirandish-Gozal L, Miano S, Bruni O, Ferri R, Pagani J, Villa MP, Gozal
D. Reduced NREM sleep instability in children with sleep-disordered
breathing. Sleep 2007; 30:450-457.
Ai J, Gozal D, Li L, Wead WB, Chapleau MW, Wurster R, Yang B, Li H,
Liu R, Cheng ZJ. Degeneration of vagal efferent axons and terminals in
cardiac ganglia of aged rats. J Comp Neurol. 2007;504:74-88.
Lin M, Liu R, Gozal D, Wead WB, Chapleau MW, Cheng ZJ. Chronic
intermittent hypoxia impairs baroreflex control of heart rate but enhances
heart rate responses to vagal stimulation in anesthetized mice. Am. J.
Physiol. (Heart and Circul. Physiol.) 2007; 293(2):H997-H1006.
Gozal D, McLaughlin Crabtree V, Sans Capdevila O, Witcher LA,
Kheirandish-Gozal L. C reactive protein, obstructive sleep apnea, and
cognitive dysfunction in school-aged children. Am J Respir Crit Care
Med 2007; 176:188-193.
Gozal D, Sans Capdevila O, Kheirandish-Gozal L, McLaughlin Crabtree
V. Apolipoprotein E e4 allele, neurocognitive dysfunction, and obstructive
sleep apnea in school-aged children. Neurology 2007; 69:243-249.
Chi L, Ke Y, Luo C, Gozal D, Liu R. Depletion of reduced glutathione
enhances motor neuron degeneration in vitro and in vivo. Neuroscience.
2007; 144:991-1003.
Lin S, Walker J, Xu L, Gozal D, Yu J. Behaviors of pulmonary sensory
receptors during development of acute lung injury in the rabbit. Exp
Physiol. 2007; 92:749-755.
Montgomery-Downs HE, Crabtree VM, Sans Capdevila O, Gozal D.
Infant feeding methods and childhood sleep-disordered breathing.
Pediatrics 2007; 120(5):1030-1035.
Hambrecht VS, Vlisides PE, Row BW, Gozal D, Baghdoyan HA, Lydic
R. Cholinergic and opioid activation of G proteins in rat hippocampus:
modulation by hypoxia. Hippocampus 2007; 17(10):934-942.
Soukhova-O’Hare GK, Schmidt MH, Nozdrachev AD, Gozal D. A novel
mouse model for assessment of sexual function. Physiol Behav 2007;
91:535-543.
Goldbart AD, Mager E, Veling MC, Goldman JL, Kheirandish-Gozal
L, Serpero LD, Piedimonte G, Gozal D. Neurotrophins and tonsilllar
hypertrophy in children with obstructive sleep apnea. Pediatr. Res. 2007;
62(4):489-494.
Redline S, Budhiraja R, Kapur V, Marcus CL, Mateika JH, Mehra R,
Parthasarthy S, Somers VK, Strohl KP, Sulit LG, Gozal D, Wise MS,
Quan SF. The scoring of respiratory events in sleep: reliability and validity.
J Clin Sleep Med 2007; 3:169-200.
Grigg-Damberger M, Gozal D, Marcus CL, Quan SF, Rosen CL, Chervin
RD, Wise M, Picchietti DL, Sheldon SH, Iber C. The visual scoring of
sleep and arousal in infants and children. J. Clin Sleep Med. 2007; 3:201-
240.
Zhang SXL, Searcy TR, Wu Y, Gozal D, Wang Y. Tissue-specific
expression of mouse monocarboxylate transporter 2 is mediated by
alternative promoters. Physiol Genomics 2007; 32(1):95-104.
Gozal D, Kheirandish-Gozal L, Serpero LD, Sans Capdevila O, Dayyat
E. Obstructive sleep apnea and endothelial function in school-aged
non-obese children: effect of adenotonsillectomy. Circulation 2007;
116(20):2307-2314.
16
17
Ai J, Epstein PN, Gozal D, Yang B, Wurster R, Cheng ZJ. Nucleus
ambiguus projections to cardiac ganglia of mice and rats: morphology
and topography. Neuroscience 2007; 142(2):163-168.
Gu H, Lin M, Liu J, Gozal D, Scrogin KE, Wurster R, Chapleau MW,
Cheng ZJ. Functional changes in baroreceptor afferent, central, and
efferent components of the baroreflex circuitry in anesthetized F344
young-adult rats following chronic intermittent hypoxia. Am. J. Physiol.
(Heart and Circul. Physiol.) 2007; 293(5):H2809-H2818.
Shan X, Chi L, Ke Y, Luo C, Qian SY, St Clair D, Gozal D, Liu R.
Manganese superoxide dismutase protects mouse cortical neurons from
chronic intermittent hypoxia-mediated oxidative damage. Neurobiol Dis.
2007; 28(2):206-215.
Kheirandish-Gozal L, Sans Capdevila O, Kheirandish E, Gozal D.
Elevated liver enzymes in children at risk for obstructive sleep apnea.
Chest 2008; 133:92-99.
Sans Capdevila O, Dayyat E, Kheirandish-Gozal L. Gozal D. Prevalence
of epileptiform activity in healthy children during sleep. Sleep Med 2008;
9(3):303-309.
Gozal D, Serpero LD, Sans Capdevila O, Kheirandish-Gozal L. Systemic
inflammation in non-obese children with obstructive sleep apnea. Sleep
Med. 2008; 9(3):254-259.
Gozal D, Kheirandish-Gozal L, Sans Capdevila O, Dayyat E, Kheirandish
E. Prevalence of recurrent otitis media in habitually snoring school-aged
children. Sleep Med 2008; 9(5):549-54.
Li RC, Morris MW, Lee SK, Pouranfar F, Wang Y, Gozal D. Neuroglobin
protects PC12 cells against oxidative stress. Brain Res. 2008; 1190:159-
166.
Trochet D, De Ponctual L, Straus C, Gozal D, Trang H, Landrieu P,
Munnich A, Lyonnet S, Gaultier C, Amiel. Germinal mutation and somatic
mosaic of phox2b in late onset central hypoventilation syndrome. Am J
Resp Crit Care Med 2008; 177(8):906-911.
Gozal D, Kheirandish-Gozal L. Cardiovascular morbidity in obstructive
sleep apnea: Oxidative stress, inflammation, and much more. Am J Resp
Crit Care Med. 2008; 177(4):369-375.
Sans Capdevila O, Kheirandish-Gozal L, Dayyat E, Gozal D. Pediatric
obstructive sleep apnea: Complications, management, and long-term
outcomes. Proc Am Thor Soc 2008; 5(2):274-282.
\Carvalho Bos S, Gomes A, Clemente V, Marques M, Pereira AT, Maia
B, Soares MJ, Cabral AS, Macedo A, Gozal D, Azevedo MH. Sleep,
behavioral, and emotional problems in children: a population-based
study. Sleep Med 2008; (in press)
Khalyfa A, Sans Capdevila O, Boazza M, Serpero LD, Kheirandish-Gozal
L, Gozal D. Genome-wide gene expression profiling in children with
obstructive sleep apnea. Sleep Med 2008; (in press)
Wu W, Nilesh DB, Strollo PJ, Kovkarova-Naumovski E, Ryter SW, Reeves
SR, Dayyat E, Wang Y, Choi AMK, Gozal D, Kaminski N. Network
analysis of temporal effects of intermittent- and sustained hypoxia on rat
lungs. Physiol Genomics 2008; (in press)
Lin L, Ai J, Chapleau MW, Liu R, Gozal D, Wead WB, Wurster R, Cheng
ZJ. Structural remodeling of nucleus ambiguus projections to cardiac
ganglia following chronic intermittent hypoxia in C57BL/6J mice. J.
Comp. Neurol. 2008; 509(1):103-117.
Gozal D, Sans Capdevila O, McLaughlin Crabtree V, Serpero LD,
Witcher LA, Kheirandish-Gozal L. Plasma insulin growth factor 1 levels
and cognitive dysfunction in school-aged children with obstructive sleep
apnea. Sleep Medicine 2008 (in press)
Monchanin G, Serpero LD, Connes P, Tripette J, Wouassi D, Francina
A, Massarelli R, Gozal D, Thiriet P, Martin C. Plasma levels of adhesion
molecules ICAM-1 and VCAM-1 in athletes with sickle cell trait with or
without a-thalassemia during endurance exercise and recovery. Clin.
Hemorheology and Microcirc. 2008; (in press)
Soukhova-O’Hare GK, Ortines RV, Gu Y, Nozdrachev AD, Prabhu
SD, Gozal D. Postnatal intermittent hypoxia and developmental
programming of hypertension in SHR: Role of ROS and L-Ca2+
channels. Hypertension 2008; 52(1):156-162.
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Kheirandish-Gozal L, Gozal D. Intranasal budesonide treatment in
children with mild obstructive sleep apnea syndrome. Pediatrics 2008;
122(1):e149-155.
Gozal D, Sans Capdevila O, Kheirandish-Gozal L. Metabolic alterations
and systemic inflammation in obstructive sleep apnea among nonobese
and obese pre-pubertal children. Am J Resp Crit Care Med 2008;
177(10):1142-1149.
Zhang SXL, Miller JJ, Stolz D, Serpero LD, Zhao W, Gozal D, Wang
Y. Type I epithelial cells are the main target of whole-body hypoxic
preconditioning in the lung. Am J. Resp. Cell. Mol. Biol. 2008; (in press)
Yan B Soukhova-O’Hare GK, Li L, Lin Y, Gozal D, Wead WB, Wurster
RD, Cheng ZJ. Attenuation of heart rate control and neural degeneration
in nucleus ambiguus (NA) following chronic intermittent hypoxia (CIH) in
young adult Fischer 344 rats. Neuroscience 2008; 153(3):709-720.
Sans Capdevila O, Crabtree VM, Kheirandish-Gozal L, Gozal D.
Increased morning brain natriuretic peptide levels in children with
nocturnal enuresis and sleep disordered breathing: A community-based
study. Pediatrics 2008; 121(5):e1208-1214.
Roure N, Mediano O, Duran J, Garcia Rio J, de la Peña M, Capote F,
Teran J, Masa JF, Alonso ML, Corral J, Sánchez-Armengol A, Martinez C,
Barceló A, Gozal D, Barbé F. Daytime sleepiness and polysomnography
in obstructive sleep apnoea patients. Sleep Medicine 2008 (in press)
Roure N, Gomez S, Mediano O, Duran J, de la Peña M, Capote F,
Teran J, Masa JF, Gozal D, Barbé F. Influencia del sexo en las variables
clínicas y polisomnográficas del síndrome de apneas del sueño. Arch
Bronconeumol. 2008;44(11):607-10
Soukhova-O’Hare GK, Shah ZA, Lei Z, Nozdrachev AD, Rao CV, Gozal
D. Erectile dysfunction in a murine model of sleep apnea. Am J Resp Crit
Care Med 2008; 178(6):644-650.
Reeves SR, Simakajornboon N, Gozal D. The role of nitric oxide in the
neural control of breathing. Respir. Physiol. & Neurobiol. 2008; (in press)
Serpero LD, Kheirandish-Gozal L, Dayyat E, Goldman Jl, Kim J, Gozal
D. A mixed cell culture model for assessment of proliferation in tonsillar
tissues from children with obstructive sleep apnea or recurrent tonsillitis.
Laryngoscope 2008 (in press)
Associate Professor
Department of Pediatrics
Department of Pharmacology & Toxicology
School of Medicine
Evelyne Gozal, Ph.D.
Research Activities:
Oxygen deprivation affecting cellular survival frequently occurs in
cerebrovascular disorders, pulmonary diseases, sleep apnea, and
nervous system injury such as 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. The balance of these pathways may determine cellular 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 and supporting tissue, and their modulation by stress-induced
proteins may provide novel therapeutic strategies for diseases involving
insufficient 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.
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.
• Protein-protein interactions in signaling complexes induced by
hypoxia.
• 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.
Grants Funded:
Role: Principal Investigator Project 1
Title: Mechanisms of Plasticity and repair after SCI, Project 1: Heat
shock proteins in spinal cord neural survival
Funding Agency: NIH/ National Center for Research Resources
Direct Costs Funded: $ 902,020
Role: Co-Investigator
Title: Modulation of Neutrophil Apoptosis by Akt-Hsp27 Signalosome
Funding Agency: National Institute of Allergy and Infectious Diseases
Direct Costs Funded: $ 900,000
Peer-reviewed Publications:
Machaalani R, Arlotto M, Waters KA, Gozal E, Berger F, Dematteis M.
A novel method of tissue collection and storage: Validation using SELDI
–TOF MS analysis. Clin. Chem.53 (7): 1387-1389 (2007).
Dematteis M, Julien C, , Guillermet C, Sturm N, Lantuejoul S, Mallaret
M, Levy P, Gozal E. Intermittent hypoxia induces Early functional and
structural cardiovascular remodeling in mice. Am. J. Resp. Crit. Care
Med. 177: 227-235, (2008).
Research Activities:
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 definition and clarification of developmental
signaling pathways critical for normal embryogenesis as well as
identification of foci for perturbation and attendant fetal abnormalities.
Current studies—selected specifics outlined briefly 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.
Robert M. Greene, Ph.D.
They grow up
so quickly
Professor and Chair
Department of Molecular, Cellular &
Craniofacial Biology
School of Dentistry
Director
Birth Defects Center
Distinguished University Scholar
19
• Transcriptional coactivators and craniofacial & neural tube
development.
• Transcriptional coactivators and folate-mediated development.
• Cigarette smoke-induced intrauterine growth retardation &
postnatal cognitive deficits.
• TGFß/Smad signaling mechanisms in embryonic craniofacial
development.
Grants Funded:
Role: Principal Investigator
Title: Transcriptional Coactivators and Pregnancy Outcomes
Funding Agency: NIH (NICHD)
Direct Costs Funded: $1,321,365
Role: Principal Investigator
Title: Nutritional Epigenetics and Orofacial Development
Funding Agency: NIH
Direct Costs Funded: $900,000
Role: Principal Investigator
Title: Molecular Determinants of Developmental Defects
Funding Agency: NCRR Center for Biomedical Research Excellence
Direct Costs Funded: $12,072,292
Role: Principal Investigator
Title: Birth Defects Center Postdoctoral
Fellowship
Funding Agency: Kosair Charities
Direct Costs Funded: $45,000
Peer-Reviewed Publications:
Singh S, Yin X, Mukhopadhyay P,
Pisano MM and Greene RM. Mitogen
activated protein kinase signaling
pathways in developing orfacial tissue.
Birth Defects Research, Part A: Clinical
and Molecular Teratology 79:35-44
(2007). PMID: 17177285
Bhatacherjee V, Mukhopadhyay P, Singh S, Johnson C, Philipose J,
Warner C, Hackmiller R, Greene RM and Pisano MM. Neural crest
and mesoderm lineage-dependent gene expression in developing
orofacial tissue. Differentiation 75:463-477 (2007). PMID: 17286603
Warner D, Horn K, Mudd L, Webb CL, Greene RM, Pisano MM.
PRDM16/MEL1: A novel Smad binding protein expressed in murine
embryonic orofacial tissue. Biochimica Biophysica Acta – Molecular
Cell Research 1773:814-820 (2007). PMID: 17467076
Warner DR, Greene RM, Pisano MM. Target Assessment-PRDM16
(MEL1). Targeted Proteins Database (TPdb) (available on-line) (2008).
Greene RM, Pisano MP. Perspectives in orofacial cleft research II:
Molecular Mechanisms. In: Comprehensive Cleft Care, Edit. Losee JE,
Kirschner RE., McGraw-Hill (accepted for publication) (2008).
Mukhopadhyay P, Webb C, Warner D, Greene RM, Pisano, MM. BMP
signaling dynamics in embryonic orofacial tissue. J Cellular Physiol
216:771-779 (2008). PMID: 18446813
Esposito ER, Horn KH, Greene RM, Pisano MM. An animal model
of cigarette smoke-induced in utero growth retardation. Toxicology
246:193-202 (2008). PMID: 18316152
Horn K, Horn KH, Esposito ER, Greene RM, Pisano MM. The effect
of cigarette smoke exposure on developing folate binding protein-2
null mice. Reproductive Toxicology 26:203-209.
Warner DR, Smith HS, Webb CL, Greene RM, Pisano MM.
Expression of Wnts in the developing murine secondary palate.
Internat J Develop Biol (accepted for publication).
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 - (accepted for publication).
Why can’t I shave?
20
Research Activities:
The research in the laboratory continued to focus on the mechanisms
and genes responsible for two forms of congenital stationary
night blindness (CSNB). Mice deficient in transmission between
photoreceptors and second order neurons were analyzed. Mutations
in the alpha -1F subunit of voltage dependent calcium channels
(Cacn1af) and the metabotropic glutamate receptor 6 (Grm6) subunit
were characterized. Mutations in the Cacn1af subunit result in the
dendrites of post synaptic neurons extending abnormally, while the
retinal morphology of the Grm6 mutant mice is normal. In a third model
of CSNB, the nob mouse, studies showed that there is abnormal
development resulting in spontaneous bursting of retinal ganglion cells.
These mice also fail to form center surround organization of retinal
ganglion cells, which is thought to be important in vision. Transgenic
rescue of the phenotype of the nob mouse by expression of a
EYFP:nyctalopin fusion protein, showed that the nyctalopin was only
required at the first synapse to fully restore vision. The availability of this
line of mice should allow the function of nyctalopin to be determined.
A second project has established an international zebrafish mutant
mapping resource. This facility identified the gene responsible for
17 mutant lines of fish and provided chromosomal locations for
an additional 34 to investigators world wide. This facility is greatly
increasing the rate at which mutant zebrafish genes are identified.
Grants Funded:
Role: Principal Investigator
Title: Isolation of congenital stationary night blindness gene
Funding Agency: NIH
Direct Costs Funded: $286,573
Role: Collaborator (Mervis PI)
Title: Genotype/phenotype correlations in Williams Syndrome
Funding Agency: NIH
Direct Costs Funded: $700,000
Associate Professor
Department of Biochemistry
School of Medicine
Ronald Gregg, Ph.D.
Role: Principal Investigator
Title: Zebrafish Mutant
Mapping Facility
Funding Agency: NIH
Direct Costs Funded:
$237,119
Peer-reviewed
Publications:
Maddox DM, Vessey KA,
Yarbrough GL, Invergo BM, Cantrell DR, Inayat S, Balannik V, Hicks
WL, Hawes NL, Byers S, Smith RS, Hurd R, Howell D, Gregg RG,
Chang B, Naggert JK, Troy JB, Pinto LH, Nishina PM, McCall MA.
Allelic variance between GRM6 mutants, Grm6nob3 and Grm6nob4
results in differences in retinal ganglion cell visual responses. J Physiol.
In press (2008).
McCall M, Gregg RG. Comparisons of structural and functional
abnormalities in mouse b-wave mutants. J Physiol. In press (2008)
Marshall CR, Young EJ, Pani AM, Freckmann ML, Lacassie Y, Howald
C, Fitzgerald KK, Peippo M, Morris CA, Shane K, Priolo M, Morimoto
M, Kondo I, Manguoglu E, Berker-Karauzum S, Edery P, Hobart HH,
Mervis CB, Zuffardi O, Reymond A, Kaplan P, Tassabehji M, Gregg
RG, Scherer SW, Osborne LR. Infantile spasms is associated with
deletion of the MAGI2 gene on chromosome 7q11.23-q21.11. Am J
Hum Genet. 83:106-11 (2008).
Lee J, Willer JR, Willer GB, Smith K, Gregg RG, Gross JM. Zebrafish
blowout provides genetic evidence for Patched1-mediated negative
regulation of Hedgehog signaling within the proximal optic vesicle of the
vertebrate eye. Dev Biol. 319:10-22 (2008).
Gregg RG, Kamermans M, Klooster J, Lukasiewicz PD, Peachey
NS, Vessey KA, McCall MA. Nyctalopin expression in retinal bipolar
cells restores visual function in a mouse model of complete X-linked
congenital stationary night blindness. J Neurophysiol. 98:3023-33
(2007)
Palmer CA, Hollis DM, Watts RA, Houck LD, McCall MA, Gregg RG,
Feldhoff PW, Feldhoff RC, Arnold SJ. Plethodontid modulating factor,
a hypervariable salamander courtship pheromone in the three-finger
protein superfamily. FEBS J. 274:2300-10 (2007).
21
22
Research Activities:
Overview of selected laboratory investigatory areas:
• Molecular epidemiology, cancer genetics, etiology and prevention,
pharmacogenetics/genomics, personalized medicine, and
functional genomics.
• Identification of individuals genetically susceptible to the
development of cancer from environmental and occupational
chemicals in order to focus treatment and prevention strategies
on those at greatest risk.
• Understanding of the genetic causes for drug failure and/or
drug toxicity in order to optimize clinical drug therapy for each
individual patient.
• The mechanistic and clinical consequences of genetic variation in
the biotransformation of carcinogens and drugs.
Grants Funded:
Role: Program Leader (Cancer Prevention & Control)
Title: James Graham Brown P20 Application
Funding Agency: NIH/NCI
Total Costs Funded: $1,328,613
Role: Principal Investigator
Title: Pharmacogenetics of drug and carcinogen metabolism
Funding Agency: NIH/NCI
Total Costs Funded: $509,635
Role: Principal Investigator
Title: Metabolism and toxicity of aromatic
amines associated with hair dyes
Funding Agency: Procter and Gamble, Inc.
Total Costs Funded: $310,885
Role: Principal Investigator
Title: Characterization of NAT1 overexpression in breast tumors
Funding Agency: NIH/NCI
Total Costs Funded: $113,749
Role: Mentor/Co-Investigator
Title: Genetic polymorphisms in 5'-UTR of human NAT1 and NAT2
Funding Agency: NIH/NIEHS
Total Costs Funded: $145,022
Professor and Chair
Department of Pharmacology and
Toxicology
School of Medicine
Role: Principal Investigator
Title: Pharmacogenetics of drug and carcinogen metabolism
Funding Agency: NIH/NCI
Total Costs Funded: $1,724,900
Role: Principal Investigator
Title: UofL Environmental Health Sciences Training Program
Funding Agency: NIH/NIEHS
Total Costs Funded: $697,188
Role: Mentor
Title: Cancer Education Grant Program
Funding Agency: NIH /NCI
Total Costs Funded: $557,437
Role: Center Investigator
Title: Center for Environmental Genomics and Integrative Biology
Funding Agency: NIH
Direct Costs Funded: $4,440,000
Role: Co-Investigator on Project 1
Title: Cardiovascular toxicity of environmental aldehydes
Funding Agency: NIH/NIEHS
Total Costs Funded: $6,986,060
Role: Principal Investigator
Title: NAT1 and NAT2 Genotype Determinations
in Cancer Patients and Controls
Funding Agency: MD Anderson Cancer
Center (pass through of NCI funding)
Total Costs Funded: $60,000
Role: Director, Pharmacogenetics Core Laboratory
Title: Center for Pediatric Clinical Pharmacology Research
Funding Agency: NIH/NICHD
Total Costs Funded: $2,248,000
Role: Student Mentor
Title: Summer Environmental Health Sciences Training Program
Funding Agency: NIEHS
Total Costs Funded: $158,355
David W. Hein, Ph.D.
Role: Sub-project Principal Investigator
Title: Nashville Breast Health Study
Funding Agency: Vanderbilt University (pass through of NCI funding)
Total Costs Funded: $134,006
Role: Co-investigator
Title: A pharmacogenetic approach to prostate cancer susceptibility
Funding Agency: NCI
Total Costs Funded: $148,000
Role: Investigator/Mentor
Title: Planning Grant for Louisville Clinical
and Translational Science Award
Funding Agency: NIH
Total Costs Funded: $220,000
Role: Principal Investigator
Title: NAT1 and NAT2 Metabolism Studies with Hair Dye Arylamines
Funding Agency: Procter and Gamble, Inc.
Total Costs Funded: $100,000
Role: Co-Investigator
Title: Polymorphic genes of detoxification
enzymes as risk factors for PSP
Funding Agency: UofL Center for Environmental
Genomics and Integrative Biology
Total Costs Funded: $30,000
23
Role: Mentor
Title: N-acetyltransferase 1 polymorphism and breast cancer risk
Funding Agency: Department of Defense
Breast Cancer Research Program
Total Costs Funded: $92,442
Peer-reviewed Publications:
Zang, Y., Zhao, S., Doll, M.A., States, J.C. and Hein, D.W.: Functional
characterization of the A411T (L137F) and G364A (D122N) genetic
polymorphisms in human N-acetyltransferase 2. Pharmacogenetics
and Genomics 17: 37-45, 2007.
Husain, A., Zhang, X., Doll, M.A., States, J.C., Barker, D.F. and Hein,
D.W.: Identification of N-acetyltransferase 2 (NAT2) transcription start
sites and quantitation of NAT2-specific mRNA in human tissues. Drug
Metabolism and Disposition 35: 721-727, 2007. (Epub February 7).
Metry, K.J., Zhao, S., Neale, J.R., Doll, M.A., States, J.C., McGregor,
W.G., Pierce Jr., W.M., and Hein, D.W.: 2-amino-1-methyl-6-
phenylimidazo [4,5-b]pyridine (PhIP)-induced DNA adducts and
genotoxicity in chinese hamster ovary (CHO) cells expressing human
CYP1A2 and rapid or slow acetylator N-acetyltransferase 2. Molecular
Carcinogenesis 46: 553-563, 2007. (Epub February 12).
Walraven, J.M., Trent, J.O. and Hein, D.W.: Computational and
experimental analyses of mammalian arylamine N-acetyltransferase
structure and function. Drug Metabolism and Disposition 35: 1001-
1007, 2007. (Epub March 19).
Zang, Y., Doll, M.A., Zhao, S., States, J.C. and Hein, D.W.: Functional
characterization of single nucleotide polymorphisms and haplotypes of
human N-acetyltransferase 2. Carcinogenesis 28: 1665-1671, 2007.
(Epub April 13).
Rothman, N., Garcia-Closas, M., and Hein, D.W.: Commentary:
Reflections on G.M. Lower and colleagues’ 1979 study associating
slow acetylator phenotype with urinary bladder cancer: metaanalysis,
historical refinements of the hypothesis, and lessons learned.
International Journal of Epidemiology 36: 23-28, 2007.
Lubin, J.H., Kogevinas, M., Silverman, D., Malats, N., Garcia-Closas,
M., Tardon, A., Hein, D.W., Garcia-Closas, R., Serra, C., Dosemeci,
M., Carrato, A., and Rothman, N.: Evidence for an intensitydependent
interaction of NAT2 acetylation genotype and cigarette
smoking in the Spanish Bladder Cancer Study. International Journal of
Epidemiology 36: 236-241, 2007.
24
Morton, L.M., Bernstein, L., Wang, S.S.,
Hein, D.W., Rothman, N, Colt, J.S., Davis,
S., Cerhan, J.R., Severson, R.K., Welch,
R., Hartge, P., and Zahm, S.H.: Hair dye use,
genetic variation in N-acetyltransferase 1 (NAT1)
and 2 (NAT2), and risk of non-Hodgkin lymphoma.
Carcinogenesis 28: 1759-1764, 2007. (Epub May
23).
Mahid, S.S., Colliver, D.W., Crawford, N.P.,
Martini, B.D., Doll, M.A., Hein, D.W., Cobbs, G.A.,
Petras, R.E. and Galandiuk, S.: Characterization of
N-acetyltransferase 1 and 2 polymorphisms and haplotype
analysis for inflammatory bowel disease and sporadic colorectal
carcinoma. BMC Medical Genetics 8: 28, 2007. (Epub May 30).
Walraven, J.M., Barker, D.F., Doll, M.A. and Hein, D.W.: Tissue
expression and genomic sequences of rat N-acetyltransferases rNat1,
rNat2, rNat3, and functional characterization of a novel rNat3*2 genetic
variant. Toxicological Sciences 99: 413-421, 2007. (Epub June 12)
Husain, A., Zhang, X., Doll, M.A., States, J.C., Barker, D.F. and Hein,
D.W.: Functional analysis of the human N-acetyltransferase 1 major
promoter: Quantitation of tissue expression and identification of critical
sequence elements. Drug Metabolism and Disposition 35: 1649-1656,
2007. (Epub June 25).
Bendaly, J., Zhao, S., Neale, J.R., Metry, K.J., Doll, M.A., States, J.C.,
Pierce Jr., W.M. and Hein, D.W.: 2-Amino-3,8-dimethylimidazo-[4,5-f]
quinoxaline-induced DNA adduct formation and mutagenesis in DNA
repair deficient CHO cells expressing human CYP1A1 and rapid or slow
acetylator N-acetyltransferase 2. Cancer Epidemiology, Biomarkers &
Prevention 16: 1503-1509, 2007.
Husain, A., Loehle, J.A. and Hein, D.W.: Clinical pharmacogenetics in
pediatric patients. Pharmacogenomics 8: 1403-1411, 2007.
Jiao, L., Doll, M.A., Hein, D.W., Bondy, M.L., Hassan, M.M., Hixson,
J.E., Abbruzzese, J.L., and Li, D.: Haplotype of N-acetyltransferase 1
and 2 and risk of pancreatic cancer. Cancer Epidemiology, Biomarkers
& Prevention 16: 2379-2386, 2007.
Ravoori, S., Feng, Y., Neale, J.R., Jeyabalan, J., Srinivasan, C.,
Hein, D.W. and Gupta, R.C.: Dose-dependent reduction of
3,2’-dimethyl-4-aminobiphenyl-derived DNA adducts in colon
and liver of rats administered celecoxib. Mutation Research
638: 103-109, 2008. (Epub September 14, 2007).
Wakefield, L., Cornish, V., Long, H., Kawamura,
A., Zhang, X., Hein, D.W., and Sim, E.: Mouse
arylamine N-acetyltransferase 2 (Nat2) expression
during embryogenesis; a potential marker for the
developing neuroendocrine system. Biomarkers 13:
106-118, 2008. (Epub September 25, 2007).
Zhu, Y. and Hein, D.W.: Functional effects of single
nucleotide polymorphisms in the coding region of human
N-acetyltransferase 1. The Pharmacogenomics Journal 8: 339-348,
2008. (Epub October 2, 2007).
Feng, Y., Neale, J.R., Doll, M.A. and Hein, D.W.: Chemoprevention
of arylamine-induced colorectal aberrant crypts. Experimental Biology
and Medicine 233: 71-75, 2008.
Walraven, J.M., Trent, J.O. and Hein, D.W.: Structurefunction
analyses of single nucleotide polymorphisms in human
N-acetyltransferase 1. Drug Metabolism Reviews 40: 169-184, 2008.
Shin, A., Shrubsole, M.J., Rice, J.M., Cai, Q., Doll, M.A., Long, J.,
Smalley, W.E., Shyr, Y., Sinha, R., Ness, R.M., Hein, D.W. and Zheng,
W.: Meat intake, heterocyclic amine exposure, and metabolizing
enzyme polymorphisms in relation to colorectal polyp risk. Cancer
Epidemiology, Biomarkers & Prevention 17: 320-329, 2008.
Hein, D.W., Boukouvala, S., Grant, D.M., Minchin, R.F. and Sim,
E.: Changes in consensus arylamine N-acetyltransferase (NAT) gene
nomenclature. Pharmacogenetics and Genomics 18: 367-368, 2008.
Martin, R.C.G., Barker, D.F., Doll, M.A., Pine, S., Mechanic L.,
Bowman, E.D., Harris, C.C. and Hein, D.W.: Manganese superoxide
dismutase gene coding region polymorphisms lack clinical incidence in
general population. DNA and Cell Biology 27: 321-323, 2008. (Epub
May 8).
David W. Hein, Ph.D., continued
25
Suzuki, H., Morris, J.S., Li Y., Doll, M.A., Hein, D.W., Liu, J., Jiao,
L., Hassan, M.M., Day, R.S., Bondy, M.L., Abbruzzese, J.L., and
Li, D.: Interaction of the cytochrome P4501A2, SULT1A1, and NAT
gene polymorphisms with smoking and dietary mutagen intake in
modification of the risk of pancreatic cancer. Carcinogenesis 29: 1184-
1191, 2008. (Epub May 21).
Walraven, J.M., Zang, Y., Trent, J.O. and Hein, D.W.: Structure/
function evaluations of single nucleotide polymorphisms in human
N-acetyltransferase 2. Current Drug Metabolism 9: 471-486, 2008.
Zhou, G., Li, X., Hein, D.W., Xiang, X., Marshall, J.P., Prabhu, S.D. and
Cai, L.: Metallothionein suppresses angiotensin II-induced nicotinamide
adenine dinucleotide phosphate oxidase activation, nitrosative stress,
apoptosis, and pathological remodeling in the diabetic heart. Journal
of the American College of Cardiology 52: 655-666, 2008.
Neale, J.R., Smith, N.B., Pierce Jr., W. M., and Hein, D.W.: Methods
for aromatic and heterocyclic amine carcinogen-DNA adduct analysis
by liquid chromatography-tandem mass spectrometry. Polycyclic
Aromatic Compounds 28: 402-417, 2008..
Morton, L.M., Wang, S.S., Cozen, W., Linet, M.S., Chatterjee, N.,
Davis, S., Severson, R.K., Colt, J.S., Vasef, M.A., Rothman, N., Blair,
A., Bernstein, L., Cross, A.J., De Roos, A. J., Engels, E.A., Hein, D.W.,
Hill, D.A., Kelemen, L.E., Lim, U., Lynch, C.F., Schenk, M., Wacholder,
S., Ward, M.H., Zahm, S.H., Chanock, S.J., Cerhan, J.R., and Hartge,
P.: Etiologic heterogeneity among non-Hodgkin lymphoma subtypes.
Blood (Epub September 16, 2008).
Hein, D.W., Bendaly, J., Neale, J.R., and Doll, M.A.: Systemic
functional expression of N-acetyltransferase polymorphism in the F344
Nat2 congenic rat. Drug Metabolism and Disposition 36: 2452-2459,
2008 (Epub September 17).
Barker, D.F., Walraven, J.M., Ristagno, E.H., Doll, M.A. and Hein, D.W.:
Quantitative tissue and gene specific differences and developmental
changes in Nat1, Nat2 and Nat3 mRNA in the rat. Drug Metabolism
and Disposition 36: 2445-2451, 2008. (Epub September 17, 2008).
Kennedy, M.J., Loehle, J.A., Griffin, A.R., Doll, M.A., Kearns,
G.L., Sullivan, J.E. and Hein, D.W.: Association of the histamine
N-methyltransferase C314T (Thr105Ile) polymorphism with atopic
dermatitis in Caucasian children. Pharmacotherapy28: 1495-1501,
2008.
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 (Epub September 26, 2008).
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 (Epub October 8, 2008).
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-2-hydroxytoluene in vivo. Toxicology and
Applied Pharmacology (Epub November 28, 2008).
Research Activities:
An important goal in birth defects research is to derive the architecture
and function of developing systems as biological networks. At the Birth
Defects Center, Dr. Knudsen’s laboratory used genomic and systems
biology to understand the developmental consequences of prenatal
exposures to alcohol and environmental toxicants. With vast genomics
data and bioinformatics tools now at hand, efforts are underway to
reverse-engineer gene regulatory networks (GRNs) that underlie birth
defects and developmental abnormalities. Dr. Knudsen’s research
focuses on ‘virtual tissues’ whereby computational embryology and
developmental computational techniques are being implemented to
understand toxicity processes in complex biological systems. A longterm
goal of this new research is to develop a sophisticated computer
model of a mammalian embryo that can be used to help scientists
better understand the prenatal risks posed by chemicals and other
environmental stressors. This project is using computers to develop
models of GRNs and reconstruct embryonic tissues in silico (http://
www.epa.gov/ncct/v-Embryo/). ‘Virtual tissue’ technology enables
researchers to interact with a computer-simulated environment of
specific embryonic tissues. The ability to perform complex operations
on simulated system gives insight to conditions hard to evaluate due to
time, scale, and cost (monetary and animal). Challenges for technology
development include a knowledgebase to extract, organize, and store
data (database) and facts (literature) about the tissue in a computable
form, and a simulation engine for multi-scale models to study how
different mechanisms interact at one level and cause effects at a
higher level. Validated computational (in silico) models of the embryo
may someday help scientists integrate in vitro data at different scales
molecules to phenotype as well as to help link toxicity pathways with
prenatal developmental effects in vivo.
26
Adjunct Professor
Department of Molecular, Cellular &
Craniofacial Biology
School of Dentistry
Developmental Systems Biologist
Thomas B. Knudsen, Ph.D.
Professor and Director
Division of Maternal-Fetal Medicine
Department of Obstetrics, Gynecology
& Women’s Health
School of Medicine
Jeffrey C. King, M.D.
Research Activities:
The Division of Maternal-Fetal Medicine
includes 5 sub-specialty trained
obstetricians along with their support
staff of sonographers, medical assistants,
counselors, and others that provide 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, identification of patients at risk for preterm labor,
hypertension management, prenatal diagnosis, patient safety initiatives,
and various maternal outcomes.
Peer-reviewed 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.
Grants Funded:
Role: Co-Principal Investigator with Dr. Michele Pisano
Title: Response Signatures of Alcohol Related Birth Defects
Funding Agency: NIH
Direct Costs Funded: $221,582
Role: Co-Principal Investigator with Dr. Michele Pisano
Title: Perinatal Breast Cancer Programming: fat and estrogens
Funding Agency: NIH
Direct Costs Funded: $104,000
Role: Co-Investigator; PI Ken Ramos
Title: Center for Environmental Genomics and Integrative Biology
Funding Agency: NIH
Role: Co-Investigator; PI Denis Knane
Title: Epithelial cell TLRs in disease susceptibility
Funding Agency: NIH
Peer-reviewed Publications:
Green ML, Singh AV, Zhang Y, Nemeth KA, Sulik KK and Knudsen TB.
Reprogramming of genetic networks during initiation of the fetal alcohol
syndrome. Devel Dynam 236: 613-631 (2007).
Singh AV, Knudsen KB and Knudsen TB. Integrative Analysis of the
mouse embryonic transcriptome. Bioinformation 1: 24-30 (2007).
Singh AV, Rouhka EC, Rempala GA, Bastian CD and Knudsen TB.
Integrative database management for mouse development: systems
and concepts. Birth Defects Res C (2007) 81: 1-19.
Calabrese EJ, et al., Knudsen TB, et al. Biological Stress Response
Terminology: Integrating the concepts of adaptive response and
preconditioning stress within a hormetic dose-response framework.
Toxicol Appl Pharmacol 222:122-128 (2007).
Deaciuc IV, Song Z, Peng X, Barve SS, Song M, He Q, Knudsen TB,
Singh AV, and McClain CJ. Genome-wide transcriptome expression
in the liver of a mouse model of high carbohydrate diet-induced liver
steatosis and its significance for the disease. Hepatol International
2:39-49 (2008).
Barthold JS, McCahan, Singh AV, Knudsen TB, Si X, Campion L and
Akins RE. Altered expression of muscle and cytoskeleton-related genes
in a rat strain with inherited cryptorchidism. J Androl. 29:352-366
(2008).
Datta S, Turner D, Singh R, Ruest LB, Pierce WM Jr and Knudsen
TB. Fetal Alcohol Syndrome (FAS) in C57BL/6 mice detected through
proteomics screening of the amniotic fluid. Birth Defects Res A 82:177-
186 (2008).
Knudsen TB and Kavlock RJ. Comparative bioinformatics and
computational toxicology. In: Developmental Toxicology 3rd edition. (B
Abbott and D Hansen, editors) New York: Taylor and Francis, Chapter
12 pp 311-360 (2008)
27

Zhang H, Denhard LD, Zhou H, Liu L, Lan ZJ. 0610009K11Rik, a
testis-specific and germ cell nuclear receptor-interacting protein.
Biochem Biophysic Res Commun 366(4):898-904 (2008).
Reddy P, Liu L, Adhikari D, Jagarlamudi K, Rajareddy S, Shen Y, Du
C, Tang W, Hämäläinen T, Peng SL, Lan ZJ, Cooney AJ, Huhtaniemi
I, and Liu K. Oocyte-specific deletion of Pten causes activation of the
entire pool of primordial follicles. Science 319(5863):611-613 (2008).
Li Z, Zhang H, Denhard LA, Liu LH, Zhou H, Lan ZJ. Reduced white
fat mass in adult mice bearing a truncated Patched 1. Int J Biol Sci
4(1):29-36 (2008).
Lan ZJ, Zhang H, Zhou H, Liu J, Denhard LA, Cooney AJ. (2008)
Oocyte-specific expression of fibroblast growth factor 8 and its role in
ovarian development. 41st Annual Meeting of the Society for the Study
of Reproduction, Kona, HW, May 27-30, 2008.
28
Research Activities:
Our laboratory is mainly interested in understanding the functional
roles of germ cell-expressing genes in male and female reproduction.
Currently we are investigating the roles of fibroblast growth factors,
ring/zinc finger proteins and hedgehog signaling molecules in those
processes. We combine mouse genetic, molecular and cellular
approaches to address the roles of these genes during reproduction.
Characterization of the functions of these genes in the gonads would
provide new leads for development of contraceptive agents, and
diagnostic reagents and therapeutic medicines for infertility. In addition,
we are also interested in exploring the role of ring/zinc finger proteins in
steroid nuclear receptor action in the ovary and mammary gland in vivo
and in vitro. The potential roles of human orthologs for ring/zinc finger
proteins in breast and ovarian cancers are also being investigated.
Grants Funded:
Role: COBRE supported junior investigator
Title: The role of germ-cell expressing genes in reproduction
Funding Agency: National Institutes of Health/
National Center for Research Resources
Direct Costs Funded: $157,500
Peer-reviewed Publications:
Zhao H, Li Z, Cooney AJ, Lan ZJ. Orphan nuclear receptor function in
the ovary. Frontier in Bioscience 12:3398-3405 (2007).
Assistant Professor
Department of Molecular, Cellular and
Craniofacial Biology
School of Dentistry
Zi-Jian Lan, Ph.D.
Research Activities:
My researches aim to investigate the function roles of three crosslyrelated
receptor tyrosine kinases, Tyro3, Axl, MerTK (TAM), particularly
the functions of the MerTK in regulation of the retinal pigmental
epithelial (RPE) cell for phagocytic clearance of the spent photoreceptor
out segments. MerTK null mutation causes human retinitis pigmentosa
(RP), a group of inherited retinal degenerative diseases with a
worldwide prevalence of 1:3500, and eventually leads to complete
blindness. Our goal aims to elucidate the molecular mechanism of
the MerTK regulation on RPE phagocytosis through studies of the
MerTK regulated candidate genes that may in turn affect RPE function
or through investigations of the MerTK-mediated signal transduction
pathways that subsequently regulate cytoskeletonal rearrangement
during process of the phagocytosis. With progresses of our studies,
we expect to gain new knowledge and understanding of the RPE
function, which will allow us to develop and implement new therapies
for treatment of RP caused by RPE dysfunction.
Grants Funded:
Role: Principal Investigator
Title: MerTK regulation of the PTTG and RPE phagocytosis
Funding Agency: NIH/NEI
Direct Costs Funded: $1,250,000
Peer-reviewed Publications:
Wang H, Chen S, Chen Y, Wang H, Wu H, Tang H, Xiong W, Ma J, Ge
Y, Lu Q, Han D. The role of Tyro 3 subfamily receptors in the regulation
of hemostasis and megakaryocytopoiesis. Haematologica. 92:643-650
(2007).
Xiong W, Chen Y, Wang H, Wu H, Lu Q, Han D. Gas6 and the Tyro 3
receptor tyrosine kinase subfamily regulate the phagocytic function of
Sertoli cells. Reproduction 135:77-87 (2008).
Assistant Professor
Department of Ophthalmology and
Visual Sciences
School of Medicine
Qingxian Lu
Research Activities:
Scholarship this past year was focused on the development of Near
Infrared Spectroscopy (NIRS) as an assessment tool in the Neonatal
Intensive Care Unit as well as the presentation of findings from some
pilot work achieved while working under the P20 from the Birth Defects
Center. I am now participating in a neonatal registry for infants that
is using NIRS technology. The focus of my research trajectory is on
novel approaches to care in the NICU; the paper on Bubble CPAP
with a graduate student fell under this domain. A new schemata for
categorizing interventions in the NICU was developed using a Delphi
Technique at the national level and was published and presented. This
schemata will be useful during observations in the NICU of procedures
performed by nurses and physicians, and will aid in the analysis of ROM
data. Pilot data from a previous R15 was published that will direct
future funding efforts. Currently I am collaborating with a Psychiatrist,
a Neonatologist, a Chemist, a Chemical Engineer, a Statistician, a
Social Psychologist, and two PhD Communication faculty on several
interprofessional teams. These collaborations are evidenced in my
publication record. One commentary on published research in my field
was solicited and published. I just completed a 3 year term as the Chair
of the Research Committee of my professional association and currently
serve as the Research Section Editor for the affiliated journal.
As the Associate Dean for Graduate Academic Affairs in the School
of Nursing, I direct 5 Master of Science in Nursing Program Tracks as
well as a PhD in Nursing. We are also in the process of developing
a practice doctorate that will be submitted for review to the School
for Interdisciplinary and Graduate Studies this academic year. Active
in university affairs, I serve on the university and the HSC technology
Associate Professor and Associate Dean
for Graduate Academic Affairs
School of Nursing
29
Rosalie Mainous, Ph.D.*
Research Activities:
Dr. Dennis L. Molfese is an internationally recognized expert on the use
of brain electrical recording techniques to study the emerging relationship
between brain development and cognitive processes. He has six active
NIH, NASA and DOE research grants that fund research into the early
identification and treatment of babies and young children at risk for
developing reading and math disabilities, the precursors of dyslexia with
Dr. Victoria Molfese at the University of Louisville, the long-term impact
of prenatal exposure to cocaine on child cognitive development with Dr.
Linda Mayes at the Yale University Child Study Center, an investigation
into the brain correlates of successful language interventions with
children who have selective language impairments with Dr. Paul Yoder of
the Kennedy Center at Vanderbilt University, and a study of the impact
of mild sleep reductions on children’s neural processing with Dr. David
Gozal in the Department of Pediatrics at the University of Louisville.
NASA funds his research into changes in brain processing that occur
during extended space travel.
Dr. Molfese received his Ph.D. in Psychology from the Pennsylvania State
University in 1972. He is currently a Distinguished University Scholar
and Professor in the Birth Defects Center at the University of Louisville.
Dr. Molfese served as a member and Chair of numerous of NIH grant
review panels on Learning Disabilities. He is co-director of one of 15
national laboratories that make up the
National Institutes of Health Reading
and Learning Disabilities Research
Network. He is a Fellow of the
American Psychological Association
and the American Psychological
Society and serves as Editor-in-
Chief for the scientific journal,
Developmental Neuropsychology.
He was recently recognized as
“Psychologist of the Year” (2007) by
the Kentucky Psychological Association. In addition to his collaborations
and consultations with a number of laboratories in the USA, Finland, and
The Netherlands, Dr. Molfese also serves as a consultant on infant and
child development issues to the country of Belize, C.A.
Grants Funded:
Role: Principal Investigator
Title: Impact of Sleep, Microgravity and
Stress on Cognition & the Brain
Funding Agency: NASA
Direct Costs Funded: $1,839,383
30
Dennis L. Molfese, Ph.D.
committees and am the point person in the SON ROM on technology.
As a Neonatal Nurse Practitioner, I am active at the national level in
several venues as the director of the NNP program and participate in
the development of educational standards for NNPs. I am developing a
mechanism for the evaluation of online teaching and advocate for new
technology in the teaching arena including the use of Tegrity, wikis, blogs,
and videoconferencing in real time. I currently teach Genetics, Evidence
Based Practice, and Neonatal Pathophysiology at the master’s level ROM
and direct doctoral students in Leadership and Research Practicums.
Grants Funded:
Role: Principal Investigator
Title: Nursing Workforce Development Grant
Funding Agency: US Department of Health and Human Services
Direct Costs Funded: $36,538
Peer-reviewed Publications:
Bonner, K & Mainous, R. O. The nursing care of the infant receiving
bubble CPAP therapy. Advances in Neonatal Care 8: 78-95 (2008).
Mainous, R. O. & Looney, S. A pilot study of changes in cerebral blood
flow velocity, resistance and vital signs following a painful stimulus in the
premature infant. Advances in Neonatal Care 7: 88-104 (2007).
Mainous, R. O. Commentary on Venipuncture Verses Heel Lance
for Blood Sampling in Term Neonates, (Systematic review), Evidence-
Based Nursing 11: 72 (2008).
Martin, C. A., Mainous, A. G. III, Ford, H. H., Mainous, R.O., Slade, S., Martin,
D., & Omar, H. A., Alcohol, impulsive behavior and guns. In Adolescence and
Alcohol, Tel Aviv: Freund Publishing House, p. 25-31 (2007).
Mainous, R.O. A delphi study on categorization of noxious stimuli in
the NICU, Advances in Neonatal Care 8: 135 (2007).
* Dr. Mainous’ full title is: Dr. Rosalie Mainous, Ph.D., ARNP, NNP-BC
Professor
Department of Molecular, Cellular &
Craniofacial Biology
Distinguished University Scholar
School of Dentistry
Role: Principal Investigator
Title: Space Flight and Exploration: The impact on perception,
cognition, sleep, and brain physiology
Funding Agency: NASA
Direct Costs Funded: $1,984,000
Role: Principal Investigator
Title: Sleep and Psychophysiological Function in Children
Funding Agency: NIH: National Heart, Lung, and Blood Institute
Direct Costs Funded: $1,837,500
Role: Co-Investigator
Title: ERP and Behavioral predictors of language intervention
Funding Agency: NIDCD
Direct Costs Funded: $2,340,268
Role: Co-Investigator
Title: Scaling Up the Implementation of a Pre-Kindergarten
Mathematics Curriculum in Public Preshool Programs
Funding Agency: U.S. Department of Education
Direct Costs Funded: $2,000,000
Role: Principal Investigator
Title: Neonatal Dyslexia Screening Device for Clinical Use
Funding Agency: NICHD
Direct Costs Funded: $126,000
Role: Co-Investigator
Title: Cocaine-Exposed Children & ERP Studies of Neurocognition
Funding Agency: NIH/NIDA
Direct Costs Funded: $1,850,000
Role: Co-Investigator
Title: Scaling Up the Implementation of a Pre-Kindergarten
Mathematics Curriculum in Public Preschool Programs
Funding Agency: U.S. Department of Education
Direct Costs Funded: $2,000,000
Peer-reviewed Publications:
Molfese, D. L., Molfese, V. J., & Pratt, N. L. (2007). The Use Of Event-
Related Evoked Potentials To Predict Developmental Outcomes. In M.
de Haan (Ed.), Infant EEG and Event-Related Potentials. Psychology
Press: Hove, UK.
Molfese, D., Molfese, V. & Molfese, P. (2007). Relation Between Early
Measures Of Brain Responses To Language Stimuli and Childhood
Performance On Behavioral Language Tasks. In D. Coch, G. Dawson,
& K. Fischer (Eds). Human Behavior and the Developing Brain, Second
Edition: Atypical Development (pp 191-211). New York: Guilford
Publications, Inc.
Key, A., Ferguson, M., Molfese, D., Peach, K., Lehman, C. & Molfese
V. (2007). Smoking during pregnancy affects speech discrimination
ability in newborn infants. Environmental Health Perspectives, 115(4),
623-629.
Molfese, V., Molfese, D., Beswick, J., Jacobi-Vessels, J., Molfese, P.,
Molnar, A., Wagner, M., Haines, B. (2008). Event Related Potentials To
Identify Language and Reading Skills. Topics in Language Disorders,
28, 28-45.
31
Research Activities:
Victoria J. Molfese is the Ashland/Nystrand Chair in Early Childhood
Education and Professor in the Department of Teaching and Learning
at the University of Louisville. She is also the Director of the Center
for Research in Early Childhood. She has published journal articles,
books, and book chapters in the area of cognitive development in
infants, children and adults. She has received grants in support of
research activities, including an NIH funded longitudinal research grant
on electrophysiological and behavioral predictors of language and
cognitive development in children from birth through age 13 years.
Additional grant funding was received to study the development of
reading and mathematical skills in preschool children, the development
of personality in twin infants and their parents, and to study the impacts
of sleep disturbances on the behaviors of children as well as adults.
Her work has been funded by grants from National Institutes of Health,
March of Dimes, U.S. Department of Education, U.S. Department
of Health and Human Services, the Kellogg Foundation, and NASA.
Research is currently underway on early predictors of reading and
mathematic abilities in both infants and preschool children, home and
school characteristics that influence learning in early childhood, the
development of interventions for infants and preschool children to
mitigate the development of learning disabilities, and an investigation
of the influence of school-based and home-based intervention on the
development of mathematical and early literacy skills of preschool
children at risk due to poverty.
Grants Funded:
Role: Co-Investigator
Title: Scaling Up the Implementation of a Pre-Kindergarten
Mathematics Curriculum in Public Preschool Programs
Funding Agency: U.S. Department of Education
Direct Costs Funded: $2,000,000
Role: Co-Investigator
Title: Impact of Sleep, Microgravity and
Stress on Cognition and the Brain
Funding Agency: NASA
Direct Costs Funded: $1,980,000
Role: Co-Investigator
Title: The Impact Of The Microgravity Environment On Perception,
Cognition, Sleep, and Brain Physiology
Funding Agency: NASA
Direct Costs Funded: $1,980,000
Ashland/Nystrand Chair in Early
Childhood Education
Associate Editor
Developmental Neuropsychology
Center for Research in Early Childhood
College of Education and Human
Development
32
Victoria J. Molfese Ph.D.
Kook, H., Gupta, L., Kota, S., Molfese, D.L., & Lyytinen, H. (2008),
“An Offline/Real-Time Artifact Rejection Strategy to Improve the
Classification of Multi-Channel Evoked Potentials, Pattern Recognition,
41, 1985-1996.
Molfese, D., Molfese, V., Barnes, M., Warren, C., & Molfese, P. (2008).
Familial predictors of dyslexia: Evidence from preschool children with
and without familial dyslexia risk. In V. Berninger, A. Fawcett, G. Reid
& L Siegel (Eds). Handbook of Dyslexia. New York Sage Publications,
99-120.
Tan, A. & Molfese, D. L. (2009). ERP Correlates of Noun and Verb
Processing in Preschool-Age Children. Biological Psychology, 80 (1), (In
press).
Molfese, D., Molfese, V., & Beswick, J., Jacobi-Vessels, J., Molfese,
P. & Starkey, G. (2008). Dynamic Links Between Emerging Cognitive
Skills and Brain Processes. Special Issue on Neurobiological
and experiential dimensions of dyslexia: Multiple perspectives.
Developmental Neuropsychology, 33(6), 682–706.
Role: Investigator
Title: Sleep and Sleep Disorders in Children
Funding Agency: National Institutes of Health
Direct Costs Funded: $1,800,000
Peer-reviewed Publications:
Jung, E., Molfese, V., Beswick, J., Jacobi-Vessels, J., & Molnar,
A. (in press). Growth of Cognitive Skills in Preschoolers: Impacts of
Sleep Habits and Learning-Related Behaviors. Early Education and
Development.
Molfese, D., Molfese, V., & Beswick, J., Jacobi-Vessels, J., & Molfese,
P. (in review). Dynamic Links Between Emerging Cognitive Skills and
Brain Processes. Special Issue on Neurobiological and experiential
dimensions of dyslexia: Multiple perspectives. Developmental
Neuropsychology.
Jung, E., Larson, A. E., Molfese, V. J., & Thompson, C. (2008).
Research-based teacher candidate dispositions assessment system:
Moving forward. Journal of Education for Teaching, 34, 155-156.
Brown, E. T., Molfese, V. & Molfese, P. (2008). Preschool Student
Learning in Literacy and Mathematics: Impact of Teacher Experience,
Qualifications, and Beliefs On An At-Risk Sample. Journal of Education
for Students Placed At Risk, 13, 106-126.
Molfese, V., Molfese, D., Beswick, J., Jacobi-Vessels, J., Molfese, P.,
Molnar, A., Wagner, M., Haines, B. (2008). Event Related Potentials To
Identify Language and Reading Skills. Special Issue on Language and
Dyslexia. Topics in Language Disorders, 28, 28 – 45.
Molfese, V., Beswick, J., Molnar, A., Jacobi-Vessels, J., & Gozal, D.
(2007). The Impacts of Sleep Duration, Problem Behaviors and Health
Status on Letter Knowledge in Pre-Kindergarten Children. Child Health
and Education: An Interdisciplinary Journal, 1, 41-53.
Ferguson, M., Key, A.P.F., Lehman, C., Molfese, D., Molfese V., & Peach,
K., (2007). Smoking during pregnancy affects speech processing ability
in newborn infants. Environmental Health Perspectives 115, 623-629.
Kulakowski, E., Chronister, L., Molfese, V., Slocum, J.M., Studman, C.,
& Waugaman, P. (2007). International research infrastructure and the
impact of export control regulations. Journal of Research Administration,
38, 231-240.
Molfese, V., Cervelin, J., & Miller, P. (2007). Voice of Experience:
Demystifying the NIH Proposal Review Process. Journal of Research
Administration, 38, 94-102.
33
Endocrinology and Metabolism. In addition, Dr. Moore has been
actively involved in presenting his research locally as well as at scientific
meetings and though manuscript publications. During 2007-2008 he
presented at four separate meetings, published several peer reviewed
manuscript 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
Peer-reviewed Publications:
S.J. Winters, D. Ghooray, Y. Fujii, J. P. Moore, Jr., J. R. Nevitt, and S.S.
Kakar. Transcriptional Regulation of Follistatin Expression by GnRH in
Mouse Gonadotroph Cells: Evidence of a Role for cAMP Signaling.
Mol Cell Endocrinol. 2007 Jun
15;271(1-2):45-54. Epub 2007
Apr 4. Erratum in: Mol Cell
Endocrinol. 2007 Sep 30;276(1-
2):88-9.
El-Naggar SM, Malik MT, Martin
A, Moore JP, Proctor M, Hamid
T, Kakar SS. Development of
cystic glandular hyperplasia of
the endometrium in Mullerian
inhibitory substance type
II receptor-pituitary tumor transforming gene transgenic mice. J
Endocrinol. 2007 Jul;194(1):179-91.
Chen YC, Cochrum RK, Tseng MT, Ghooray DT, Moore JP, Winters SJ,
Clark BJ. Effects of CDB-4022 on Leydig Cell Function in Adult Male
Rats. Biol Reprod. 2007 Dec;77(6):1017-1026. Epub 2007 Aug 22.
J.P. Moore, Jr., and S.J. Winters. Weaning and the Developmental
Changes in Follicle-Stimulating Hormone, Pituitary Adenylate Cyclase-
Activating Polypeptide, and Inhibin B in the Male Rat. Biol Reprod.
2008 Apr;78(4):752-60.
J. Chanal, C-C Chen, M.J. Rane, J.P. Moore, Jr., M.T. Barati, Y. Song,
B.C. Villafuerte. Regulation of Insulin-Response Element Binding
Protein-1 in Obesity and Diabetes: Potential Role in Impaired Insulin-
Induced Gene Transcription. Endocrinology. 2008 149:4829-36 Epub
Jun 19.
Research Activities:
Dr. Moore’s laboratory is interested in the regulation of pituitary
hormones, particularly the sex regulating hormones, the gonadotropins.
The gonadotropins, luteinizing hormone (LH) and follicle stimulating
hormone (FSH), are both produced and secreted from the same cell
type however, the secretion of one gonadotropin often predominates.
He has previously 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 influences of social interactions and milk
borne products on the timing of puberty in the male.
In August of 2007, Dr. Moore was awarded his first R01 grant from
the National Institutes of Child Health and Development entitled “Role
of PACAP in the Male Fetal Pituitary”. The preliminary data presented
in his application was obtained through direct funding through the
COBRE previously awarded to the Birth Defects Center. In July of 2007,
Dr. Moore accepted a faculty position in the Department of Anatomical
Sciences and Neurobiology at the University of Louisville School of
Medicine and maintains a joint
appointment in the Department
of Medicine, Division of
The pituitary
secretes hormones
that are essential
to growth and
reproduction.
Assistant Professor
Department of Anatomical Sciences
and Neurobiology
School of Medicine
Joseph Patrick Moore Jr., Ph.D.
34
Research Activities:
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 specific research interests are to examine the role
of the nuclear transcriptional regulators (Smads and Ids), coactivators
(CBP and p300) and corepressors (c-Ski and Sno) in craniofacial
growth and anomalies, to analyze the role of growth factors like TGF-ßs
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 profiles” 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 specific 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-loophelix
transcription factors in orofacial ontogenesis
and (3) Epigenetics and Fetal Alcohol Syndrome.
Grants Funded:
Role: Principal Investigator
Title: Epigenetics and Fetal Alcohol Syndrome
Funding Agency: Kentucky Science &
Engineering Foundation
Direct Costs Funded: $20,000
Assistant Professor
Department of Molecular, Cellular &
Craniofacial Biology
School of Dentistry
Partha Mukhopadhyay
Role: Principal Investigator
Title: BMP Regulated Transcription in Embryonic Palatal Tissue
Funding Agency: The Cleft Palate Foundation
Direct Costs Funded: $10,000
Peer-reviewed Publications:
Bhattacherjee V, Mukhopadhyay P, Singh S, Johnson C, Philipose
JT, Warner CP, Greene RM, Pisano MM. Neural crest and mesoderm
lineage-dependent gene expression in orofacial development.
Differentiation 75: 463-477 (2007).
Marian MJ, Mukhopadhyay P, Borchman D, Tang D, Paterson CA.
Regulation of sarco/endoplasmic and plasma membrane calcium
ATPase gene expression by calcium in cultured human lens
epithelial cells. Cell Calcium. 41:87-95 (2007).
Marian M, Mukhopadhyay P, Borchman D, Tang D, Paterson
CA. Plasma membrane Ca2+-ATPase isoform expression in
human cataractous lenses compared to age matched clear lenses.
Ophthalmic Res 40:86-93 (2008).
Mukhopadhyay P, Webb CL, Greene RM, Pisano MM. BMP
signaling dynamics in embryonic orofacial tissue. J Cell Phys
216:771-779 (2008).
Marian MJ, Mukhopadhyay P, Borchman D, Tang D and Paterson
CA. The effect of hydrogen peroxide on sarco/endoplasmic and
plasma membrane calcium ATPase gene expression in cultured
human lens epithelial cells. The Open Ophthalmology Journal
2:123-129 (2008).
35
36
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.
Peer-reviewed Publications:
Myers, Steven R. and Ali, M. Yeakub. Haemoglobin as a biomarker for
tobacco-related nitrosamines, Biomarkers 12(8): 1 – 15, 2007.
Myers, S.R., Bioalkylation of Benz(a)anthracene: Implications for
Carcinogenesis, Journal of Polycyclic Aromatic Compounds, 27(4): 311 –
337, 2007.
Myers, S.R., Ali, M. Y., Wright, T., and Cunningham, C. Benzo(a)
pyrene Metabolism: Role of Bioalkylation, Journal of Polycyclic Aromatic
Compounds 27(4):339 – 359, 2007.
Myers, S.R. and Ali, M. Y., Determination of Tobacco Specific Hemoglobin
Adducts in Smoking Mothers and NewBorn Babies by Mass Spectrometry.,
Biomarker Insights 2:269–282, 2007.
Myers, S.R. and Spinnato, J.A., Tissue distribution and elimination of N
-methyl- N -2,4,6-tetranitroaniline (tetryl) in rats, Archives of Toxicology,
81(12): 841-848, 2007.
Myers, S.R. and Spinnato, J.A., Metabolism, tissue distribution, and
pharmacokinetics of N-methyl-N-2,4,6-tetranitroaniline (tetryl) Environmental
Toxicology and Pharmacology, 24(3): 206 -211, 2007.
Sumanasekera, W. K., Ivanova, M. M., Johnston, B. J., Dougherty, S. M.,
Sumanasekera, G. U., Myers, S. R., Ali, M. Y., Kizu, R., and Klinge, C. M.,
Rapid effects of diesel exhaust particulate extracts on intracellular signaling in
human endothelial cells. Toxicology Letters, 174(1-3): 61-73, 2007.
Myers, S.R., Zamora, R., Ali, M. Y., Cunningham, C. R., Wright, T., and
Weeks, J. Analysis of Polycyclic Aromatic Hydrocarbons in Amniotic Fluid
Samples from Smokers and Nonsmokers, Journal of Polycyclic Aromatic
Compounds 28(1): 39 – 66, 2008.
Myers, S.R., Hurst, H.E., Cunningham, C., Ali. M. Y., and Wright, T.,
Kinetics of Formation of (±)-anti-7, 8-dihydroxy-9a,10a-epoxy-7, 8, 9,
10-tetrahydrobenzo[a]pyrene Adducts with Mouse and Human Hemoglobin,
Journal of Polycyclic Aromatic Compounds, 28(2):143 - 164, 2008.
Associate Professor
Department of Pharmacology &
Toxicology
School of Medicine
Steven Myers
Research Activities:
Our research examines the development and validation of biological
markers of exposure to environmental hazards, including tobacco
smoke and automobile exhaust. Specifically, we have developed and
refined 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 detoxification
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 fluid as a biomarker of carcinogen exposure detected in
the first 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.
37
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 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:
Role: Co-Principal Investigator with Dr. Thomas Knudsen
Title: Response Signatures of Alcohol Related Birth Defects
Funding Agency: NIH
Direct Costs Funded: $221,582
Role: Co-Principal Investigator with Dr. Thomas Knudsen
Title: Perinatal Programming of Breast Cancer: Fat and Estrogens
Funding Agency: NIH
Direct Costs Funded: $104,000
Role: Subproject Director
Title: Pre- and Postnatal Tobacco Smoke Exposure: Effects on
Neurocognitive Development
Funding Agency: NIH
Direct Costs Funded: $1,061,826
Role: Principal Investigator
Title: Developmental Neurotoxicity of Prenatal Environmental Tobacco
Smoke Exposure
Funding Agency: University of Louisville Center for Environmental
Genomics and Integrative Biology
Direct Costs Funded: $30,000
M. Michele Pisano, Ph.D.
Professor
Department of Molecular, Cellular &
Craniofacial Biology
School of Dentistry
Professor
Department of Pharmacology & Toxicology
School of Medicine
Research Director
Laboratory of Molecular Craniofacial
Development
University Scholar
Research Activities:
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 Kofi 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 that 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
Role: Co-Investigator
Title: Prdm16: Novel Zinc Finger Protein Linked to Palatal Clefting
Funding Agency: Kentucky Science and Engineering Foundation
Direct Costs Funded: $20,000
Role: Co-Investigator
Title: Epigenetics and Fetal Alcohol Syndrome
Funding Agency: Kentucky Science and Engineering Foundation
Direct Costs Funded: $20,000
Peer-reviewed Publications:
Singh S,Yin Y, Pisano MM, Greene RM. Molecular expression profiles
of mitogen activated protein kinase signaling pathways in craniofacial
development. Birth Defects Res A 79:35-44 (2007).
Bhattacherjee V, Mukhopadhyay P, Singh S, Johnson C, Philipose J,
Warner C, Greene RM, Pisano MM. Neural crest and mesoderm
lineage-dependent gene expression in orofacial development.
Differentiation 75:463-477 (2007).
Warner D, Horn K, Mudd L, Greene RM, Pisano MM. PRDM16/MEL1:
A novel Smad binding protein expressed in murine embryonic orofacial
tissue. Biochim Biophys Acta – Molec Cell 1773:814-820 (2007).
De Falco M, Pisano MM, De Luca A. Embryology, histology and
anatomy of mesothelium. In: Mesothelioma - From benchside to the
Clinic; Edit. Baldi, A, Nova Science Publishers, Inc, New York (2007)
ISBN 1-60021-789-3.
De Falco M, Pisano MM, De Luca A. Signaling involved in epithelialmesenchymal
transitions: from embryogenesis to cellular pathogenesis.
In: Mesothelioma - From benchside to the Clinic; Edit. A Baldi, A; Nova
Science Publishers Inc, New York (2007) ISBN: 1600217893.
38
Role: Co-Investigator; PI RM Greene
Title: Transcriptional Coactivators and Pregnancy Outcomes
Funding Agency: NIH
Direct Costs Funded: $1,321,365
Role: Co-Investigator; PI RM Greene
Title: Nutritional Epigenetics and Orofacial Development
Funding Agency: NIH
Direct Costs Funded: $900,000
Role: Co-Investigator; PI D Bayarsaihan
Title: Role of TFIIi in Craniofacial Development
Funding Agency: NIH
Direct Costs Funded: $1,000,000
Role: Principal Investigator, Mentor
Title: Nuclear Co-Activators in Developing Craniofacial Tissue
Funding Agency: NIH
Direct Costs Funded: $410,395
Role: Principal Investigator, Mentor
Title: Prenatal Tobacco Smoke Exposure and Hypoxia-Induced
Developmental Abnormalities
Funding Agency: Philip Morris Research Foundation
Direct Costs Funded: $80,000
Esposito ER, Horn KH, Greene RM, Pisano MM. An animal model
of in utero cigarette smoke induced growth retardation. Toxicology
246:193-202 (2008).
Greene, RM, Pisano MM. Chapter 73: Perspectives in orofacial cleft
research II: Molecular mechanisms. In Comprehsensive Cleft Care,
Edit. Lossee, JE and Kirschner, RE; McGraw-Hill, Ohio (2008) ISBN:
9780071481809.
Warner DR, Greene RM, Pisano MM. Target Assessment-PRDM16
(MEL1). Current Biodata - Targeted Proteins Database (TPdb) (2008)
Available online at http://currentbiodata.com
Mukhopadhyay P, Greene RM, Pisano MM. BMP signaling dynamics
in embryonic orofacial tissue. J Cell Physiol 216:771-779 (2008).
Horn KH, Esposito ER, Greene RM, Pisano MM. The effect of cigarette
smoke exposure on the development of Folbp2 null mice. Reprod Tox
26:203-209 pp-pp. (2008)
39
Research Activities:
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, specifically 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.
Grants Funded:
Role: Project Leader
Title: Aldehyde Metabolism and Cardiovascular Disease
Funding Agency: NIEHS/NIH
Direct Costs Funded: $169,385
Professor
Department of Biochemistry & Molecular
Biology
School of Medicine
Russell A. Prough, Ph.D.
Dehydroepiandrosterone induces human CYP2B6 through the constitutive
androstane receptor, Drug Metabolism and Disposition, 35, 495-501
(2007). [PMID: 17591676; PMCID pending].
D. Conklin, R. Prough and A. Bhatnagar, Aldehyde Metabolism in the
Cardiovascular System Molecular Biosystems, 2, 136-150 (2007).
V. Tamasi, S. Webb, T. Geoghegan, E. Vila, and R. Prough. PPARalpha
Regulation by Dehydroepiandrosterone, In: Proceedings of the 15th
International Conference on Cytochromes P450 – Biochemistry, Biophysics
and Functional Genomics, Medimond, Bologna, Italy, pp. 23-29 (2007).
K.C. Falkner, J.T. Ritter, and R. A. Prough, Regulation of the rat UDPglycosyltransferase
1A6 by glucocorticoids involving a cryptic glucocorticoid
response element, Drug Metabolism and Disposition, 36, 409-17 (2008)
[PMID: 18039810; PMCID pending]
V. Tamasi, K.K. Michael Miller, S.L. Ripp, E. Vila, T.E. Geoghegan, and R.A.
Prough, Phosphorylaton of Serine 6, 12, and 21 regulates murine PPARa
action, Molecular Pharmacology 73, 968-76 (2008) [ PMID: 18079279;
PMCID pending].
J. Cai, B.G. Hill, A. Bhatnagar, W.M. Pierce, Jr., and R.A. Prough,
Bioactivation and Protein Modification Reactions of Unsaturated Aldehydes,
In: Advances in Bioactivation Research (A. Elfarra, Ed.), Springer
Science+Business Media, New York, NY IN PRESS (2008).
S.J. Webb, K.C. Falkner, T.E. Geoghegan, and R.A.
Prough, Convergence of Multiple Nuclear Receptors
and Metabolic Signaling Pathways in Xenobiotic
and Nutrient Metabolism, In: Volume 2, Cellular
and Molecular Toxicology (Ed., Kenneth S.
Ramos) of the 2nd Edition of Comprehensive
Toxicology (Ed.-Chief, C.A. McQueen), IN
PRESS, Elsevier, Oxford, UK (2009).
Role: Co-Investigator
Title: Molecular Epidemiology of Environmental/Occupational Disease
Funding Agency: NIEHS/NIH
Direct Costs Funded: $228,552
Role: Co-Principal Investigator
Title: NIEHS Summer Environmental Health Sciences Training Program
Funding Agency: NIEHS/NIH
Direct Costs Funded: $28,725
Role: Mentor
Title: NIDDK Summer Endocrinology Research Training Program
Funding Agency: NIEHS/NIH
Direct Costs Funded: $28,725
Role: Director
Title: Career Development of Environmental
Health Investigators Project
Funding Agency: NIEHS/NIH
Role: Investigator
Title: DHEA: PPAR-Dependent and Independent
Mechanisms of Action
Funding Agency: NIH/NIDDK
Role: Project Leader
Title: University of Louisville’’s Clinical and
Translational Science Institute
Funding Agency: Translational Technology and Resources
Direct Costs Funded: $340,594
Peer-reviewed Publications:
K.Cameron Falkner and Russell A. Prough, Regulation of the rat
glutathione S-transferase A2 gene by glucocorticoids: Crosstalk through C/
EBPs, , Drug Metabolism Reviews, 39, 371-388 (2007) [PMID: 17786629;
PMCID pending].
Amunom, L.J. Stephens, V. Tamasi, D.J. Conklin, A. Bhatnagar, S.
Srivastava, M.V. Martin, F.P. Guengerich, and R.A. Prough, Cytochromes
P450 catalyze oxidation of a,ß-unsaturated aldehydes, Archives of
Biochemistry & Biophysics, 464, 187-96 (2007) [PMID: 17599801; PMCID
pending]
K. Kohalmy, V. Tamasi, L. Kobori, E. Sarvary, J.-M. Pascussi, P.
Porrogi, D. Rozman, R.A. Prough, U.A. Meyer, and K. Monostory,
Research Activities:
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) Identification of the molecular pathways that regulate
the early specification and differentiation of motor neurons and
oligodendrocytes. (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 interacting proteins of motor neuron and oligodendrocyte
lineage-specific homeodomain transcription factors. (4) Lineagespecific
differentiation of embryonic stem cells into motor neurons and
oligodendrocytes for spinal cord transplantation.
Grants Funded:
Role: Principal Investigator
Title: Molecular and genetic control of oligodendrocyte development
Funding Agency: NIH
Direct Costs Funded: $1, 226,157
Role: Principal Investigator
Title: Role of Olig3 bHLH transcription factor in gliogenesis
Funding Agency: NIH
Direct Costs Funded: $338,336
Professor
Department of Anatomical Sciences and
Neurobiology
School of Medicine
Matthew Qiu
41
Role: Principal Investigator
Title: Lineage analysis and signaling mechanism of oligodendrocyte
genesis
Funding Agency: National Multiple Sclerosis Society
Direct Costs Funded: $353, 516
Role: Principal Investigator
Title: Role of Olig3 in cerebellar and precerebellar development
Funding Agency: NIH
Direct Costs Funded: $354,586
Role: Principal Investigator
Title: Developmental regulation of axonal myelination by Necl
molecules
Funding Agency: National Multiple Sclerosis Society
Direct Costs Funded: $474,019
Role: Co-Investigator
Title: Transcriptional Coactivators and Pregnancy Outcomes
Funding Agency: National Multiple Sclerosis Society
Direct Costs Funded: $1, 503,187
Peer-reviewed Publications:
Liu Z, Hu X, Cai J, Liu B, Peng X, Wegner M, and Qiu M. (2007).
Induction of oligodendrocyte differentiation by Olig2 and Sox10:
evidence for reciprocal interactions and dosage-dependent
mechanisms. Dev. Biol. 302, 683-693.
Lee X, Yang Z, Shao Z, Rosenberg SS, Levesque M, Pepinsky RB,
Qiu M, Miller RH, Chan JR, Mi S (2007). NGF regulates the expression
of axonal LINGO-1 to inhibit oligodendrocyte differentiation and
myelination. J. Neurosci. 27, 220-225.
Liu B, Liu Z, Chen T, Li H, Peng X and Qiu M (2007). Selective
expression of Bhlhb5 in subsets of early-born interneurons and lateborn
association neurons in the spinal cord. Dev. Dyn. 236, 829-835
Research Activities:
Dr. Sears is Chief Psychologist and Associate Professor of Pediatrics at
the Weisskopf Child Evaluation Center. His primary research interest is
in autism. In collaboration with other U of L researchers he is involved
in studies of cytokines in autism, the neuropsychology of autism, and in
medical treatment of autism.
Grants Funded:
Role: Collaborator
Title: Aripiprazole Flexibility Dosed in the Treatment of
Children and Adolescents with Autistic Disorder
Funding Agency: Bristol-Myers Squibb
Direct Costs Funded: $106,486
Role: Collaborator
Title: Safety and Tolerability of Aripiprazole Flexibly Dosed in the
Treatment of Children and Adolescents with Autistic Disorder
Funding Agency: Bristol-Myers Squibb
Direct Costs Funded: $92,518
Peer-reviewed Publications:
Williams PG, Hersh J, Allard A, & Sears LL. A controlled study of
mercury levels in hair samples of children with autism as compared to
their typically developing siblings. Res Autism Spectr Disord 2:170-175
(2008).
Lonnie Sears, Ph.D.
Associate Professor
Department of Pediatrics
School of Medicine
42
Zhang, Y., Shields, L., Pei J., Zhang, Y., Xu, X-M. Hoskins, R.,
Cai, J., Qiu, M., Magnuson, D., Burke, D., and Shields, C. (2007).
The Feasibility of Motor Evoked Potentials, Somatosensory Evoked
Potentials, and H-Reflexes Induction in Non-sedated Rodents Using
Magnetic Stimulation. J. of Neurosci. Methods. 165, 9-17.
Chen X, Qiu M, Whittemore S, Cao Q. (2007). BMP signaling and
olig1/2 interact to regulate the differentiation and maturation of adult
oligodendrocyte precursor cells. Stem Cell. 25, 3204-3214
Zhao S, Hu X , Park J, Zhu Y, Zhu Q, Luo C, Han R, Cooper N. and
Qiu M. (2007). Selective expression of LDLR and VLDLR in myelinating
oligodendrocytes. Dev. Dyn. 236, 2708-2712.
Li J , Liu Z, Liu Q, Fu X, Cooper N, Pan Y, Li Y , Qiu M*, Shi T*. (2007).
Regulatory Network of bHLH Transcription Factors in Mouse Brain.
Genome Biology (*co-corresponding authors) 8(11):R244.
Hu J., Fu S., Wang Y., Li Y., Jiang X., Wang X, Qiu M., Lu P, Xu X.
(2008). PDGF-AA mediates oligodendrocyte lineage differentiation
through activation of Erk but not PI3K signaling pathway. Neuroscience,
151, 138-147.
Liu Z, Li H, Hu X, Yu L, Liu H, Colella R, Mower G , Chen Y, and Qiu
M. (2008). Control of precerebellar neuron development by Olig3 bHLH
transcription factor. J. Neurosci. 28:101 24-33.
Cai J, Zhang Y, Qi Y, Li H, Zhang Y, Han R, Shields CB and Qiu M.
(2008). Coordinated expression of Nkx2.2 and Nkx6.2 homeodomain
transcription factors in myelinating oligodendrocytes. Glia In revision.
Park,J, Liu B, Chen T, Li H, Hu, X, Gao J, Zhu Y, Zhu Q, Qiang B, Yuan
J, Peng X and Qiu M. Disruption of Necl-1 cell adhesion molecule
leads to delayed axonal myelination in the developing nervous system.
J. Neurosci. In press.
Research Activities:
Dr. Seelan’s principal research interests are in understanding the
genetic basis of cognitive and neurodevelopmental disorders such
as Autism. One area of active interest is to understand the molecular
biology of genes involved in myo-inositol metabolism such as myo-
Inositol Synthase and Inositol Monophosphatases 1 and 2. Myo-inositol
is an important precursor for the ‘phosphoinositide signaling’ pathway
which not only generates IP3, an important second messenger
molecule, but also activates several neuronal receptors required for
the normal functioning of the brain. Depleted myo-inositol levels are
frequently observed in the brains of patients suffering from Autism
Spectrum Disorders. Deficiencies in inositol signaling have been
implicated in the etiology of several psychiatric disorders including
Bipolar Disorder. Specifically, the discovery of novel isoforms for some
of these genes in the laboratory has rekindled renewed interest in brain
myo-inositol synthesis and regulation, subunit composition of the brain
enzymes, and identifying the transcription factors that regulate their
expression in brain. Much of this work has been done in collaboration
with Dr. R. Parthasarathy, VA Medical Center, Louisville. Another area
of interest is the epigenetic modulation of these genes in Autism and
other behavioral disorders. A role for CpG methylation in brain-specific
regulation has been established for some of these genes and CpG
methylation profiles are being
developed for normal and affected
(Autism) brain tissues to identify
critical CpG residues involved
in gene expression. Ongoing
collaborative studies with Dr. M.
F. Casanova, Dept. of Psychiatry
and Behavioral Sciences, and
Dr. Michele Pisano, Birth Defects
Center, University of Louisville,
will examine the genetic and
biochemical bases for abnormal
minicolumns observed in the
autistic brain and the effect of
environmental stressors such as maternal cigarette smoke exposure on
the cognitive abilities of the offspring. His studies are currently funded
by the COBRE mechanism and he continues to seek additional funding
support for his varied research interests. Funding from the Department
of Defense and March of Dimes grant programs are currently pending.
Ratnam Seelan, Ph.D.
Grants Funded:
Role: Sub-project Principal Investigator
Title: Effect of interneuron loss on minicolumn structure
Funding Agency: National Institutes of Health/National Center for
Research Resources; Center of Biological Research Excellence
(COBRE)
Direct Costs Funded: $120,000
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: $157,000
Peer-reviewed Publications:
Seelan RS, Khalyfa A, Lakshmanan J, Casanova MF, Parthasarathy
RN. Deciphering the lithium transcriptome: microarray profiling
of lithium modulated gene expression in human neuronal cells.
Neuroscience 151: 1184-1197 (2008).
43
Assistant Professor
Department of Molecular, Cellular &
Craniofacial Biology
School of Dentistry
Research Activities:
Much of my research activities during 2007-2008 focused on the TGFß
and Wnt signaling pathways and their role in developmental processes
during formation of the secondary palate. Defects in development of
the secondary palate lead to clefts, which affect approximately 1 in
700 births. TGFß and Wnt are both large families of cytokines with
diverse functions in embryonic and adult tissues. From earlier in vitro
studies on primary cultures of embryonic mouse palate mesenchymal
cells, we demonstrated that TGFß1 and Wnt-3a cooperate to induce
gene transcription. To follow up this observation, we obtained a grant
from the American Cleft Palate Foundation to perform high-density
microarrays to identify genes whose regulation is uniquely regulated by
both TGFß1 and Wnt-3a in combination, using a mouse model, which
is very useful because of the similarities to human palate development.
Indeed, these experiments have led to a collection of genes that are
regulated by TGFß and Wnt, and not seen with either cytokine alone.
These data provide a foundation for further analysis of the intersection
of these two pathways as it pertains to the normal sequence of events
required for proper palate development. We have also performed
a comprehensive analysis of the expression of other Wnts in the
developing mouse palate, an area that is only now beginning to be
explored in detail, and have found several display interesting patterns
of expression, suggesting specific roles. We are now in a position to
determine the functional role of this large family of proteins.
Significant progress has been made on the analysis of a protein
identified by us (PRDM16) as being involved in the TGFß signaling
pathway, and, when mutated, can lead to cleft palate in mice. There is
also evidence in humans linking mutations of PRDM16 to cleft palate.
PRDM16 is a transcription factor that has been recently demonstrated
to be a protein that can direct cell differentiation. We obtained a grant
from the Kentucky Science and Engineering Fund to further study the
role of PRDM16 in crucial cellular/developmental processes necessary
for proper palate development, such as cell proliferation, synthesis of
extracellular matrix, and fusion of the nascent palatal shelves. We are
currently in the process of further characterizing the genes regulated by
PRDM16 and its possible role in palatal bone formation.
Grants Funded:
Role: Principal Investigator
Title: Gene Discovery in Orofacial Tissue
Funding Agency: American Cleft Palate Foundation
Direct Costs Funded: $10,000
Assistant Professor
Department of Molecular, Cellular &
Craniofacial Biology
School of Dentistry
44
Role: Principal-Investigator
Title: PRDM16: A Novel Zinc Finger Protein Linked to Palatal Clefting
Funding Agency: Kentucky Science and Engineering Foundation
Direct Costs Funded: $18,191
Peer-reviewed Publications:
Warner DR, Horn KH, Mudd L, Webb CL, Greene RM, Pisano MM.
PRDM16/MEL1: A Novel Smad Binding Protein Expressed in Murine
Embryonic Orofacial Tissue. Biochimica et Biophysica Acta-Molecular
Cell Research 1773:814-820 (2007).
Warner DR, Greene RM, Pisano MM. (2007) “PRDM16-Target
Assessment” Targeted Proteins Database.
P. Mukhopadhyay P, Webb CL, Warner DR, Greene RM, Pisano MM
“BMP Signaling Dynamics in Embryonic Orofacial Tissue. Journal of
Cellular Physiology 216:771-779 (2008).
Warner DR, Smith IV HS, Webb , Greene RM, Pisano MM “Expression
of Wnts in the Developing Murine Secondary Palate” International
Journal of Developmental Biology, in press.
Dennis Warner
45
Research Activities:
Dr. Wittliff’s team explores the roles of hormones and their mimics in
human cancer, exploiting proteomics and genomics. He was among
the first to prove appearance of estrogen receptors in breast cancer
predicted a patient’s response to hormone therapy. This finding led
to collaborations with the National Surgical Adjuvant Breast Project,
establishing Tamoxifen as adjuvant therapy for breast cancer and use of
receptors as tissue biomarkers of a patient’s prognosis and response.
Wittliff’s discovery of receptor polymorphism in cancer provided
evidence of another receptor isoform, confirmed recently as ER-beta.
With NEN/DuPont, Dr. Wittliff developed the original FDA-approved kits
for assessing receptors in biopsies, celebrated as a major contribution
to laboratory medicine. His laboratory in the Brown Cancer Center was
designated the National Reference Facility for performing QA surveys
of receptor testing for historic clinical trials in North America. Focusing
expertise on other molecules exhibiting estrogen mimicry, Dr. Wittliff
and IA, Inc. patented receptor-based biosensors detecting endocrinedisrupting
compounds in the environment.
In recognition of contributions to medicine, the University of Innsbruck,
Austria awarded him, Doctor of Medicine honoris causa. More than
200 students and research fellows have trained in Dr. Wittliff’s program
in the Hormone Receptor Laboratory. He has received the Award for
Outstanding Contributions to Clinical Chemistry in a Selected Area of
Research from the American Association for Clinical Chemistry and
was given the Distinguished Scientist’s Award by the Clinical Ligand
Assay Society. In 2004, the American Cancer Society recognized his
lifetime achievements with the Goldsmith Research Excellence Award.
Recently, Dr. Wittliff served as Visiting Industry Professor at Arcturus
Applied Genomics, where research on the genomics of human breast
cancer using laser capture microdissection revealed clinically relevant
molecular signatures. These latest discoveries and his development of
a unique Tumor Marker Database and biorepository have resulted in the
filing of numerous new patents for the University of Louisville and the
licensing of his technologies.
Grants Funded:
Role: Principal Investigator
Title: A Genomic Approach for Assessing Clinical Outcome of Breast
Cancer using Cells Isolated by Laser Capture Microdissection
Funding Agency: Phi Beta Psi Sorority Research Foundation
Direct Costs Funded: $47,250
Professor
Department of Biochemistry & Molecular
Biology
Research Professor of Surgery
School of Medicine
James L. Wittliff, Ph.D., M.D.
Research Activities:
Amy I. Whitsel, MD is an active
clinician in the division of Maternal-
Fetal Medicine in the Department
of Obstetrics and Gynecology
who has board certifications in
Obstetrics and Gynecology
and Maternal-Fetal Medicine.
Her clinical and research interests
are in the prevention, detection and
management of pregnancies complicated by
congenital anomalies. Her undergraduate background
is in cell and developmental biology and her fellowship research was
in the teratogenic effects of valproic acid working with the chicken
embryo in ovo model. She enjoys assisting patients and families with
complicated pregnancies, coordinating the specialized care of the
fetus and neonate with congenital anomalies and inherited disorders
and regularly works with the Fetal Board
at Kosairs Childrens Hospital. She
is interested in collaborating in
research projects looking at the
causes of birth defects and
prevention.
Assistant Professor
Department of Obstetrics & Gynecology
Division of Maternal – Fetal Medicine
School of Medicine
Amy I. Whitsel, M.D.
46
Role: Principal Investigator
Title: The Proof of Concept Grant
Funding Agency: Office of Technology Transfer
Direct Costs Funded: $25,000
Role: Co-Principal Investigator
Title: Genomic Approach to Predicting Breast Cancer Recurrence
Funding Agency: Brown Cancer Center Pilot Project 2006
Direct Costs Funded: $37,750
Peer-reviewed Publications:
Wittliff JL, Kruer TL, Andres SA, Smolenkova IA. Molecular Signatures
of Estrogen Receptor-associated Genes in Breast Cancer Predict
Clinical Outcome. In : Hormonal Carcinogenesis V (Li JJ, Li SA, Mohla
S, Rochefort H, Maudelone T, Eds.), Springer Verlag, pp.349-357, 2008.
Kerr II, DA, Eliason JF, Wittliff JL Steroid Receptor and Growth Factor
Receptor Expression in Human Non-small Cell Lung Cancers Using
Cells Procured by Laser-Capture Microdissection. In : Hormonal
Carcinogenesis V (Li JJ, Li SA, Mohla S, Rochefort H, Maudelone T,
Eds.), Springer Verlag, pp.377-384, 2008.
Andres, S.A., Kerr II, D.A., Bumpus, S.B., Kruer, T.L., Thieman, J.W.,
Smolenkova, I.A., Wittliff, J.L. A Three-Tiered Approach for Calibration
of a Biosensor to Detect Estrogen Mimics. Adv Exp Med Biol, 614:305-
313, 2008.
Wittliff, JL, Andres SA, Kruer TL, Kerr II, DA, Erb JL Biosensors and
Molecular Signatures: Detecting Estrogen-like Therapeutics & Predicting
Clinical Outcome of Cancer. Adv Exp Med Biol, 315-322, 2008.
Role: Principal-Investigator
Title: University of Louisville component, Commercialization of
Nutraceuticals to Enhance Sustainable Agriculture in Limited Resource
Caribbean Farming Communities
Funding Agency: USAID/Clemson University
Direct Costs Funded: $97,306
Role: Core Faculty/Recruiter
Title:
Funding Agency: National Institutes of Health,
Cancer Education Grant Program, NCI
Direct Costs Funded: $356,665
Role: Investigator
Title: Podocytes and Oxidative Stress in Diabetic Kidney
Funding Agency: National Institutes of Health
Direct Costs Funded: $96,728
Role: Principal Investigator
Title: Gene Expression Profiling of Human Lung Cancer Cells Isolated
by Laser Capture Microdissection
Funding Agency: Kentucky Lung Cancer Research Program
Direct Costs Funded: $271,845
Role: Principal Investigator
Title: Optimization of a Comprehensive Database with Tissue
Processing and Evaluation for Genomic & Proteomic Analyses
Funding Agency: Asterand, Inc.
Direct Costs Funded: $105,000
Cara Cashon, Psychology & Brain
Science, College of Arts & Science
Ken Ramos, Biochemistry &
Molecular Biology, School of Medicine
Paul Tiwana, Oral & Maxillofacial
Surgery, School of Dentistry
Stephen J. Winters, Division
of Endocrinology, Metabolism &
Diabetes, School of Medicine
Photos were not avavilable for these members:
Joe Hersh, Pediatrics, School of Medicine
Carolyn Mervis, Psychology & Brain Science, College of Arts
& Science
Rachel Neal, Environmental & Occupational Health Science,
School of Public Health
Jerry Rabalais, Pediatrics, School of Medicine The Birth Defects Center acknowledges Heather L.
Jones, University of Louisville Design and Printing
Services, for graphic design on this document.
Other Members of the Birth Defects Center
The University of Louisville is an equal opportunity institution and does not discriminate against persons on the basis of race, age, religion, sex, disability, color, sexual
orientation, national origin or veteran status.
This publication was prepared by the University of Louisville and printed with state funds KRS 57.375. 167339 – 01/09
Notes
Birth Defects Center
501 S. Preston Street, Suite 301
Louisville, Kentucky 40292
502.852.7507 • 502.852.4702
www.louisville.edu/hsc/birthdefectscenter/index.htm

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