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CRS Members (A-M) ... CRS Members (N-Z)
Bartles, J. |
Bass, J. |
Baumann, W. |
Bledsoe, C. |
Brannigan, R. |
Bulun, S. |
Chatterton, R.T. |
Dunaif, A. |
Elias, S. |
Flouret, G. |
Goldberg, E. |
Hendrix, M.J.C. |
Hirsch, E. |
Horton, T.H. |
Iannaccone, P.M. | Jameson, J.L. |
Kazer, R.R. |
Kim, J |
Kuzawa, C. |
Lee, C. |
Linzer, D.I.H. |
Mayo, K.E. |
McDade, T.W. |
McKenna, K.E. |
Milad, M.P.
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James Bartles, Ph.D.
Department of Cell and Molecular Biology
Ph.D., Washington University
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The plasma membrane is the interface between the cell and the environment; it is a site where
one can find a host of specializations that appear to be remarkably well-tailored to the
needs of the cell. Examples include: plasma membrane domains; diffusion barriers;
projections such as microvilli and stereocilia; invaginations such as coated pits and
caveolae; and junctions of various types. Although these plasma membrane specializations
differ from one another in many respects, they share a common structural organization:
they are sites where elements of the cortical cytoskeleton are linked, directly or
indirectly, to transmembrane proteins of the overlying plasma membrane. The result is to
tether or cluster integral plasma membrane proteins, peripheral membrane proteins and
cytoskeletal proteins at these specific sites and afford paths along which signals can be
relayed between the cell surface and interior. The objective of our research is to
identify and characterize novel membrane and cytoskeletal proteins of plasma membrane
specializations. Much of our recent work has centered on an analysis of the plasma
membrane specializations of the cells of the male reproductive system, in particular the
domains and diffusion barriers present within the plasma membrane overlying the tail of
the mammalian spermatozoon and the intercellular junctions formed between Sertoli cells
and developing spermatids in the seminiferous epithelium.
Recent Publications:
Cesario MM, Bartles JR 1994 Compartmentalization, processing and redistribution of the plasma membrane protein
CE9 on rodent spermatozoa: relationship of the annulus to domain boundaries in the plasma
membrane of the tail. J Cell Sci 107: 561-570.
Cesario MM, Ensrud K, Hamilton DW, Bartles JR 1995 Biogenesis of the posterior-tail plasma membrane domain of
the mammalian spermatozoon: targeting and lateral redistribution of the posterior-tail
domain-specific transmembrane protein CE9 during spermiogenesis. Dev Biol 169:473-486.
Bartles JR 1995 The spermatid plasma membrane comes of age. Trends Cell Biol 5: 400-404.
Bartles JR, Wierda A, Zheng L 1996 Identification and characterization of espin, an actin-binding protein localized to
the F-actin-rich junctional plaques of Sertoli cell ectoplasmic specializations. J Cell Sci 109:1229-1239.
Sekerkova G, Zheng L, Loomis PA, Changyaleket B, Whitlon DS, Mugnaini E, Bartles JR. Espins are multifunctional actin cytoskeletal regulatory proteins in the microvilli of chemosensory and mechanosensory cells. J Neurosci. 2004 Jun 9;24(23):5445-56.
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Joe Bass, M.D., Ph.D.
Department of Medicine
M.D., Ph.D. The Medical College of Pennsylvania
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Cell and Molecular Regulation of Body Weight, Feeding and Metabolism. The focus of our research is on the effect of genetic variation and epigenetic modifiers on insulin signaling and energy homeostasis. We are using molecular genetic approaches including gene targeting and live-cell imaging to elucidate gene and biochemical networks that regulate cell survival, metabolism, and body weight. One goal of these studies is to understand how gene mutations in the insulin receptor (IR) alter its biogenesis, trafficking and cell surface targeting and to use genetic variants of the IR as a desensitizing background in which to uncover additional genes important in blood glucose regulation and neuroendocrine function. More detailed knowledge of these pathways may enable the development of rationally-designed therapies and new preclinical models that will facilitate drug testing and discovery. Our current areas of research are: 1) Function and mechanism of action of glucose-regulated molecular chaperones and heat shock proteins in receptor kinase biogenesis, 2) Tyrosine kinase signaling cascades in metabolic disease and germline mutagenesis models of type 2 diabetes, 3) Mechanisms of obesity, hyperphagia and diabetes in circadian Clock mutant mice.
Together, we now have in place in our laboratory a program that draws on approaches from molecular biology, cell biology and genetics to address fundamental mechanisms in metabolic disease. A considerable strength of this program is the availability of outstanding resources for biomedical research at Northwestern and ENH, including the Targeted Mutagenesis Facility, the Core Biotechnology facilities and extensive support for transgenic technologies and cell imaging. In addition, we have developed several productive collaborative relationships with other research groups both at Northwestern, at other Chicago area medical centers, and several other national medical centers.
Recent Publications:
Bass J, Steiner DF. Insulin receptor folding. In Insulin signaling: from cultured cells to animal models. Harwood Academic Press. Invited review, 2002.
Quing-xin, H, Wilken, J, Nakagawa, S, Ramos, MR, Jia, W, Bass J, and Weiss MA. A divergent invertebrate protein structurally resembles human insulin and activates the human insulin receptor. 2003. Genes and Development 17:826-831 (Perspective p813-818).
Reutrakul S, Hathout EH, Janner D, Hara M, Donfack J, Bass J, Refetoff S. Familial juvenile autoimmune hypothyroidism, pituitary enlargement, obesity, and insulin resistance. Thyroid. 2004 Apr;14(4):311-9.
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Gerhard Baumann, M.D.
Department of Medicine
M.D., University of Basel, Switzerland
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My laboratory is involved in growth hormone (GH) and growth factor research, particularly as it pertains
to the regulation of growth and development in human. Past research has focused on
the molecular heterogeneity of GH and the structure-function relationships of GH variants.
One result of our studies of GH variants in blood was the discovery of the GH
binding protein (GHBP) which represents a circulating extracellular domain of the GH
receptor. Measurement of the GHBP level and its regulation allowed, for the first
time, detailed studies of the function and regulation of the GH receptor in humans in
vivo. Such work had been difficult previously because of the inaccessibility of
tissues bearing GH receptors. In addition to serving as a marker for GH receptor
abundance, the GHBP substantially modulates GH action by altering the in vivo kinetics of
GH and by modulating the interaction of GH with its receptor in tissues.
Several novel insights into the molecular basis of GH resistant and GH hyper-responsive states (Laron and pygmy dwarfism, diabetes,
liver and kidney failure, hypothyroidism, malnutrition, obesity, and aging) have been
gained from the study of the GHBP and GH receptor. Furthermore, the developmental
regulation of GH responsivity throughout life has been delineated through studies of
GHBP/receptor.
Present investigations focus on the expression, tissue distribution and regulation of two splice variants of the GH receptor
in humans, on the relationship between GH receptor/GHBP endowment and somatic
growth/stature, on the mechanism and tissue sites of cleavage of the GHBP from the GH
receptor. In addition, the phenotype and biology of a recently developed GH
receptor/GHBP knockout mouse is being studied in detail.
Another area of research focuses on the GH releasing hormone (GHRH) receptor gene. This was stimulated by the discovery of a
novel severe form of dwarfism in Pakistan that is caused by nonsense mutation in GHRH
receptor gene. We are presently characterizing the genomic organization, structure
and regulation of the human GHRH receptor gene. A potential role of abnormal GHRH
receptor structure or expression in pituitary disease will be investigated.
Recent Publications:
Bauman G 1994 Growth hormone binding protein: State of the art. Endocrinol 141:1-6.
Bauman G 1995 Growth Hormone Binding Protein - Errant Receptor or Active Player? Endocrinology 136:377-378.
Maheshwari H, Sharma L., Bauman G 1996 Decline of Plasma Growth Hormone Binding Protein in Old Age. J Clin Endocrinol Metab 81:995-997.
Morales AJ, Laughlin GA, BŸtzow T, Maheshwari H, Bauman G, Yen SSC 1996 Insulin, Somatotrophic and Luteinizing Hormone Axes
in Lean and Obese Women with Polycystic Ovary Syndrome (PCOS): Common and Distinct Features. J Clin Endocrinol Metab 81:2854-2864.
Keenan BS, Richards GE, Mercado M, Dallas JS, Eakman GD, Bauman G 1996 Androgen Regulation of Growth Hormone Binding Protein (GHBP). Metabolism 45:1521-1526.
Zhou Y, He L, Bauman G, Kopchick JJ 1997 A Mouse Growth Hormone Receptor (mGHR)/Binding Protein (mGHBP) Minigene Directs Expression
of mGHR and mGHBP. J Mol Endocrinol 19:1-13.
Bauman G 1997 Editorial: Growth Without a Pituitary? - Lessons from the Guinea Pig. Endocrinology 138:3575-3576.
Popii V, Baumann G. Laboratory measurement of growth hormone. Clin Chim Acta. 2004 Dec;350(1-2):1-16.
Dschietzig T, Bartsch C, Stangl V, Baumann G, Stangl K. Identification of the pregnancy hormone relaxin as glucocorticoid receptor agonist. FASEB J. 2004 Oct;18(13):1536-8.
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Caroline Bledsoe, Ph.D.
Department of Anthropology
Ph.D., Stanford University
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Bledsoe is Professor of Anthropology and the Melville J. Herskovits Professor of African Studies at Northwestern University. Her projects in West Africa have centered on reproduction, whether social or biological: kinship and marriage; social stratification; demography and public health; ancestral traditions; fertility; child fosterage; and the cultural reworkings of literacy, knowledge, medicine, and contraceptives.
Her most formative project began a decade ago with some puzzling demographic findings on the use of Western contraceptives in rural Gambia. It revealed that while most women in the West use contraceptives in order to avoid having children, many women in sub-Saharan Africa use contraceptives for the opposite reason - to have as many children as possible. This seemingly counterintuitive fact can be explained by juxtaposing two very different cultural understandings of the life course. One is a Western model that equates aging and the ability to reproduce with the passage of linear time; the other an African model that views aging as contingent on the cumulative physical, social, and spiritual hardships of personal history, especially obstetric trauma. Inspired by the Gambian findings, Bledsoe turned an Africanist's cultural eye to the history of Western medical science, specifically the work of a Northwestern/Univ. of Chicago obstetrician in late 19th - early 20th century Chicago. Close inspections of his writings on technical medicine and on hospital architecture in Chicago, as well as his pioneering medical film-making, reveal some surprising support for the testimonies of contemporary rural African women about how the body works.
Bledsoe has produced six books and a number of articles. Her research has been supported by the National Science Foundation; the National Endowment for the Humanities; the Population Council; the Rockefeller, Ford, Mellon, Wenner Gren, and John Simon Guggenheim Foundations; and the National Academy of Sciences.
Recent Publications:
Caroline Bledsoe with contributions by Fatoumatta Banja. Contingent Lives: Fertility, Time and Aging in West Africa. 2002 University of Chicago Press, Lewis Henry Morgan Lecture Series.
Caroline Bledsoe, Susana Lerne, and Jane Guyer, eds Fertility and the Male Cycle in the Era of Fertility Decline. 2000 Clarendon: Oxford University Press.
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Robert E. Brannigan, MD
Department of Urology
M.D., Northwestern University
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Recent Publications:
Moreira SG Jr, Brannigan RE, Spitz A, Orejuela FJ, Lipshultz LI, Kim ED. Side effect profile of sildenafil citrate (Viagraª) in clinical practice. Urology. 56(3):474-6. 2000.
Gonzalez CM, Brannigan RE, Bervig T, Zelner D, Podlasek C, McKenna K, McVary KT. Protein and gene expression of nitric oxide isoforms I and III in the rat penile shaft. J Androl. 22(1):54-61. 2001.
Han M, Brannigan RE, Antenor JA, Roehl KA, Catalona WJ. Association of hemospermia with prostate cancer. J Urol. 2004 Dec;172(6, Part 1 of 2):2189-2192.
Brannigan RE. Ejaculatory disorders and lower urinary tract symptoms. Curr Urol Rep. 2004 Aug;5(4):280-6.
Jang TL, Blunt LW, Yap RL, Brannigan RE, Gonzalez CM. Large urethral diverticulum presenting as a scrotal mass: urethral reconstruction with ventral onlay buccal mucosa. J Urol. 2004 Jan;171(1):351-2.
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Serdar E. Bulun, M.D.
Department of Obstetrics & Gynecology
and a member of the Breast Cancer and Hormone Action & Signaling Transduction programs
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The laboratory research of Serdar E. Bulun, MD, focuses on studying estrogen biosynthesis and metabolism, in particular aromatase expression, in hormone-dependent human diseases such as breast cancer, endometriosis and uterine fibroids. A team of investigators works on understanding the epithelial-stromal interactions and aromotase overexpression in breast cancer tissue. Since aromatase inhibitors treat breast tumors primarily via suppressing intratumoral estrogen biosynthesis, theseeffortsare important for discovering new targets of treatment. Another teamstudies endometriosis. Basic data from this laboratory led to the introduction of aromatase inhibitors into endometriosis treatment. Human tissues and a primate model are used to elucidate cellular and molecular mechanisms responsible for the development of endometriosis. Regulation of aromatase expression is also studied in uterine fibroids, benign tumors that are dependent on estrogen for growth, by a third team.A fourth teamis investigatingthe link between progesterone action and estrogen inactivation in normal endometrium and endometriosis. Lastly,a fifth team has identified novel mutations that cause familial excessive estrogen formation syndrome. This syndrome is characterized by short stature, gynecomastia and hypogandism in males and early breast development and irregular menses in females. In this syndrome, heterozygous inversions in chromosome 15 q21, which cause the coding region of the aromatase gene to lie adjacent to constitutively active cryptic promoters that normally transcribe other genes, result in estrogen excess owing to the overexpression of aromatase in many tissues.
Recent Publications:
Fang Z, Yang S, Lydon JP, DeMayo F, Tamura M, Gurates B, Bulun SE. Intact progesterone receptors are essential to counteract the proliferative effect of estradiol in a genetically engineered mouse model of endometriosis. Fertil Steril. 2004 Sep;82(3):673-8.
Deb S, Amin S, Imir AG, Yilmaz MB, Suzuki T, Sasano H, Bulun SE. Estrogen regulates expression of tumor necrosis factor receptors in breast adipose fibroblasts. J Clin Endocrinol Metab. 2004 Aug;89(8):4018-24.
Tamura M, Deb S, Sebastian S, Okamura K, Bulun SE. Estrogen up-regulates cyclooxygenase-2 via estrogen receptor in human uterine microvascular endothelial cells. Fertil Steril. 2004 May;81(5):1351-6.
Bulun SE, Fang Z, Imir G, Gurates B, Tamura M, Yilmaz B, Langoi D, Amin S, Yang S, Deb S. Aromatase and endometriosis. Semin Reprod Med. 2004 Feb;22(1):45-50. Review.
Bulun SE, Takayama K, Suzuki T, Sasano H, Yilmaz B, Sebastian S. Organization of the human aromatase p450 (CYP19) gene. Semin Reprod Med. 2004 Feb;22(1):5-9. Review.
Ailawadi RK, Jobanputra S, Kataria M, Gurates B, Bulun SE. Treatment of endometriosis and chronic pelvic pain with letrozole and norethindrone acetate: a pilot study. Fertil Steril. 2004 Feb;81(2):290-6.
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Robert T. Chatterton, Jr., Ph.D.
Department Obstetrics and Gynecology
Ph.D., Cornell University
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Studies of the effect of stress on reproduction are presently focused on biochemical and
molecular studies of the effects of glucocorticoids on testosterone biosynthesis. We have
demonstrated a high degree of cooperativity in binding of LH to its testicular receptor.
Binding of the second molecule of LH is more than 500 times the binding affinity of the
first. Corticosterone inhibits testosterone secretion by a post-receptor mechanism and is
exerted on cytochrome P45017. The mechanism by which this effect is mediated is the topic
of current investigation.
We have investigated the
role of the adrenal androgens, particularly dehydroepiandrosterone sulfate (DS), in
rheumatoid arthritis, hemophilia, and HIV infection. In each of these conditions DS levels
decline in proportion to the severity of the condition. The role of the cytokines IL-1 and
TNF in mediation of this response and the significance of the loss of the
immunostimulatory effects of DS are under investigation.
We are continuing studies
of the effects of diet on hormone levels, particularly DS, cortisol, and estrogens, as
these hormones relate to susceptibility to breast cancer, with colleagues in the
Department of Preventive Medicine. We are also examining the relation between steroid
hormones and the formation of growth factors by breast tissue.
Studies on contraceptive
development have continued with the evaluation of tissue-specific actions of
antiestrogens. The contraceptive steroid anordrin was compared to the stilbene
antiestrogen clomiphene. Having completed all of the preclinical testing of anordrin, a
phase I clinical trial of this compound is expected to be initiated in the Clinical
Research Center at Northwestern this year. We also expect to begin studies on a steroidal
male contraceptive this year.
Recent Publications:
Chatterton RT Jr, Geiger AS, Mateo ET, Helenowski IB, Gann PH. Comparison of hormone levels in nipple aspirate fluid (NAF) of pre- and post-menopausal women: effect of oral contraceptives and hormone replacement. J Clin Endocrinol Metab. 2004 Mar;90(3):1686-91.
Hill PD, Wilhelm PA, Aldag JC, Chatterton RT Jr. Breast augmentation & lactation outcome: a case report. MCN Am J Matern Child Nurs. 2004 Jul-Aug;29(4):238-42. Review.
Chatterton RT Jr, Geiger AS, Khan SA, Helenowski IB, Jovanovic BD, Gann PH. Variation in estradiol, estradiol precursors, and estrogen-related products in nipple aspirate fluid from normal premenopausal women. Cancer Epidemiol Biomarkers Prev. 2004 Jun;13(6):928-35.
Hill PD, Aldag JC, Chatterton RT, Zinaman M. Comparison of milk output between mothers of preterm and term infants: The first 6 weeks after birth. J.Hum. Lact. 21:22-30, 2005.
Hill PD, Aldag JC, Chatterton RT, Zinaman M. Primary and secondary mediators influence on milk output in lactating mothers of preterm and term infants. J Hum. Lact. 21:138-150, 2005.
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Andrea Dunaif, M.D.
Division of Endocrinology
M.D., Columbia University College of Physicians
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The research themes of the Dunaif lab are the genetics of polycystic ovary syndrome (PCOS), the cellular molecular mechanisms of insulin resistance and the mechanisms underlying the association between metabolism and reproduction. There are three major research projects currently ongoing. The approaches range from large-scale family studies through intensive patient-oriented research to animal models and cellular and molecular biology. PCOS is the human disease model. This syndrome is characterized by increased androgen biosynthesis and disordered gonadotropin secretion. It is among the most common endocrine disorders of women, the leading cause of hormonally-related infertility and a major risk factor for type 2 diabetes mellitus.
The Genetic Basis of PCOS
This research program focuses on identifying the susceptibility genes for PCOS, performing genotype-phenotype analyses and identifying environmental and genetic factors contributing to PCOS familial phenotypes. Studies include family studies with linkage analysis and detailed analyses of reproductive function and insulin action in women with PCOS and their relatives. The approaches include statistical genetics and in vivo studies of insulin action and secretion, as well as pulsatile gonadotropin secretion. One susceptibility gene region has been identified on chromosome 19p13.2 close to the insulin receptor gene. This research is supported by the NIH-NICHD National Cooperative Program for Infertility Research.
Insulin Action and Secretion in PCOS
These studies are focused on identifying the cellular and molecular mechanisms of defects in insulin action and secretion in PCOS. Approaches include detailed in vivo studies of these parameters utilizing techniques such as the euglycemic glucose clamp, frequently sampled intravenous glucose intolerance test with minimal model analysis and graded glucose infusions. Insulin receptor signal transduction is examined in human skeletal muscle biopsies, as well as in human skeletal muscle and adipocyte cultures. Intrinsic defects in insulin receptor signaling have been identified and the mechanisms of these abnormalities are currently under investigation. These studies are supported by an NIH-NICHD-ORWH Specialized Center of Research (SCOR) on Sex and Gender Factors Affecting Women’s Health.
Fetal Origins of PCOS
These studies examine the impact of prenatal androgen exposure on insulin action in rodent, primate and sheep models. Studies include examination of lipolysis and insulin signaling in skeletal muscle and adipose tissue and the molecular mechanism of fetal programming. These studies are supported by an NIH-NICHD-ORWH Specialized Center of Research (SCOR) on Sex and Gender Factors Affecting Women’s Health.
Recent Publications
Dunaif A. Hyperandrogenemia is necessary but not sufficient for polycystic ovary syndrome. Fertil Steril 2003;2:262-3.
Urbanek M, Du Y, Silander, Collins FS, Steppan CM, Strauss JR, A Dunaif , Spielman RS, Legro RS. Variation in resistin gene promoter not associated with polycystic ovary syndrome (PCOS). Diabetes 52:214-217, 2003
Jabara S, Christenson LK, Wang CY, McCallister JM, Javitt NB, A Dunaif, Strauss JF. Stromal cells of the human postmenopausal ovary display a distinctive biochemical and molecular phenotype. J Clin Endocrinol Metab 88:484-492, 2003
Sam S, Dunaif A. Polycystic ovary syndrome: syndrome XX? Trends Endocrinol Metab. 2003;8:365-70.
Corbould A, Kim YB, Youngren JF, Pender C, Kahn BB, Lee A, Dunaif A. Insulin Resistance in the Skeletal Muscle of Women with Polycystic Ovary Syndrome Involves both Intrinsic and Acquired Defects in Insulin Signaling. Am J Physiol Endocrinol Metab. 2004 Dec 21; [Epub ahead of print]
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Sherman Elias, M.D.
John J. Sciarra Professor and Chair
Feinberg School of Medicine
M.D., University of Kentucky
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Dr. Sherman Elias is currently the Chair of the Department of Obstetrics and Gynecology, and is a clinical geneticist with over 20 years of experience. Dr. Elias was awarded his medical degree from the University of Kentucky, and completed his residency in Obstetrics and Gynecology at the University of Louisville, followed by fellowships in genetics at Yale University and Northwestern University. Dr. Elias's professional career began at Northwestern in 1978, where he held a faculty appointment until 1986, followed by appointments at Baylor College of Medicine and the University of Tennessee College of Medicine. Most recently Dr. Elias was the Head of the Department of Obstetrics and Gynecology at the University of Illinois at Chicago from 1998-2003.
Dr. Elias is distinguished internationally in reproductive endocrinology and genetics. He is a member of many prominent academic societies, including the American Association for Advancement of Science and has held important leadership positions in many professional societies. Principal Investigator on a research program to develop a non-invasive method for prenatal diagnosis using fetal cells and DNA from maternal blood. He has received continuous funding from NIH for this project since 1987.
Recent Publications:
Bischoff FZ, HZhn S, Johnson, Simpson JL, Bianchi DW, Lewis DE, Weber WD, Klinger K, Elias S, Jackson LG, Evans MI, Holzegreve W, de la Cruz F. Intact fetal cells in maternal plasma: are they really there? Lancet 361: 139-140, 2003.
Sharma A, Gussin HE, Marquz-Do D, Martinez D, Horne C, Lewis D, Hoffman R, Elias S, Simpson JL, Bischoff F. Expansion of fetal cells in the maternal circulation occurred using Progenitor RosetteSeptm enrichment procedure with IL-3, SCF and G-CSF. Am J Hum Genet 73:595, 2003.
Johnson KL, Bianchi DW, Elias S, Holzegreve W, Simpson JL, Klinger KW, NICHD Fetal Cell Isolation Study (NIFTY). Inter-laboratory comparison of fetal DNA detection from common maternal plasma samples using real-time PCR. Am J Hum Genet 73:600, 2003.
Simpson, J.L. and Elias, S. Genetics in Obstetrics and Gynecology. W.E. Saunders, Philadelphia (In Press).
Annas GJ, Elias S. Politics, morals and embryos. Nature. 2004 Sep 2;431(7004):19-20.
Elias S. The human gynome. Am J Obstet Gynecol. 2004 Jun;190(6):1528-33.
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George Flouret, Ph.D.
Department of Physiology
Ph.D., University of Wisconsin-Madison
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My research is in the area of peptide hormone synthesis, breakdown and mode of action. We
have synthesized many agonists and antagonists of LHRH, which is a peptide messenger
secreted by the brain, and which controls the secretion of LH and FSH by the anterior
pituitary. Several of the LHRH antagonists we have designed have strong antiovulatory
activity, and we are studying their susceptibility to enzymatic breakdown in various
tissues, in vivo or in vitro. We have also designed highly potent oxytocin antagonists
(OTAs), with the aim of inhibiting preterm labor. OT is one of the hormones that promote
the contractions of labor. Some of our antagonists may be the most potent OTAs yet
designed and successfully inhibit labor in the rat and the baboon. We are also
investigating the binding of OT and OTAs by uterine receptors. An understanding of the
characteristics of peptide hormone binding to receptors in target tissues as well as the
mechanisms of enzymatic degradation of these substances enhances the likelihood that
antagonists which have clinical significance may be developed both for LHRH and OT.
Recent Publications:
Fejgin MD, Pak SC, Flouret
G, Wilson Jr L 1994 Oxytocin antagonist inhibitory effect in the baboon and rat uterus may
be overcome by the use of prostaglandins. Am J Obstet Gynecol 171:1076-1080.
Fak SC, Bertoncini D,
Meyer W, Scaunas D, Flouret G, Wilson Jr L 1994 Comparison of binding affinity of oxytocin
antagonists to human and rat uterine oxytocin receptors and their correlation to the rat
uterine oxytocic bioassay. Biol Reprod 51:1140-1144.
Flouret G, Arnold ZS,
Majewski T, Petousis NH, Mahan K, Farooqui F, Blum KA, Konopinska D, Natarajan S, Crich D
1995 Antiovulatory Antagonists of LHRH related to Antide. J Peptide Sci 1:89-105.
Ahn TG, Han SJ, Cho YS, An TH, Pak SC, Flouret G. In vivo activity of the potent oxytocin antagonist on uterine activity in the rat. In Vivo. 2004 Nov-Dec;18(6):763-6.
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Erwin Goldberg, Ph.D.
Departrment of Biochemistry, Molecular Biology and Cell Biology
Ph.D., State University of Iowa
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Mammalian spermatogenesis
is a complex process of cellular differentiation, encompassing unique cytological and
molecular changes that culminate in the formation of spermatozoa. We are particularly
interested in enzymes and proteins that appear during mammalian spermatogenesis and are
unique to the spermatozoon. The best-studied example is lactate dehydrogenase (LDH-X;
LDH-C4), which is synthesized in the primary spermatocyte during the midpachytene phase of
the first meiotic division.
To understand the mechanisms regulating this remarkable
time- and cell-specific process, we have cloned and sequenced the promoter region of the ldh-c
gene. We are investigating the roles of both cis- and trans-acting
regulatory elements. Differential methylation of the CpG-rich promoter has been shown to
regulate expression negatively in tissues lacking LDH-C4.
We are also exploiting the restricted cell-type
expression of LDH-C4 to tackle problems in contraception technology and fertility control.
LDH-C4 has been successfully used as an antigen to provoke antibodies against sperm. These
antibodies interact with sperm in the female reproductive tract and effectively block
fertilization. Ongoing work is directed toward developing a contraceptive vaccine using
both synthetic peptides (comprising unique epitopes of the native protein) and recombinant
viruses encoding the human LDH-C gene as potential immunogens. We are identifying and
characterizing additional antigens capable of inducing infertility using sera derived from
infertile patients.
Recent Publications:
Li, S., Zhou, W., Doglio, L. and Goldberg, E. (1998) Transgenic mice demonstrate a
testis-specific promoter for lactate dehydrogenase (LDH). J. Biol. Chem. 273:31191-31194.
Goldberg, E. (1998) Human LDH-C peptide as an immunocontraceptive. In: Proceedings of
the 10th International Congress of Immunology, New Delhi, India, 1-6 November (Eds.
G.P.Talwar, I. Nath, N.K. Ganguly, K.V.S. Rao) Monduzzi Editore, Bologna, Italy, Publ., pp. 1327-1332.
Ambhaikar, M. and Goldberg, E. (1999) DNA-protein interactions in the CCAAT box region
of the murine lactate dehydrogenase C promoter. Molec. Reprod. Devel. 52:360-365
Xue, J.-C., and Goldberg, E. (2000) Identification of a novel testis specific leucine
rich protein. Biol. of Reprod. 62:1278-1284.
Somwaru L, Li S, Doglio L, Goldberg E, Zirkin BR. Heat-induced apoptosis of mouse meiotic cells is suppressed by ectopic expression of testis-specific calpastatin. J Androl. 2004 Jul-Aug;25(4):506-13.
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Mary J.C. Hendrix, PhD
Department of Pediatrics
PhD, George Washington University |
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The scientific objectives of the Hendrix laboratory include identifying genes which contribute to cancer metastasis and other related diseases which exhibit similar biological activities. The major goal is to define important structure/function relationships, which provide the biological basis for new therapeutic strategies. Recent studies have generated molecular classification(s) of specific tumors, and have provided new prognostic markers and novel targets for therapeutic intervention. In addition, these studies have identified certain genes that are dysregulated during cancer progression and may also be aberrant during development, resulting in birth defects. Current research activities focus on elucidating how regulatory molecules and phenotype control genes govern cell-to-cell and cell-to-matrix interactions, epithelial/mesenchymal transitions, and motility. Specific projects include signal transduction events initiated by cell adhesion molecules and growth factors; factors regulating interconversion of the tumor cell phenotype; novel three-dimensional analysis of cellular invasion through extracellular matrices; regulation of matrix metalloproteinases by tumor and stromal cell interactions; tumor angiogenesis and vasculogenesis; and the epigenetic role of the microenvironment in determining cell fate and tumor cell plasticity.
Recent Publications:
Rojas JD, Sennoune SR, Maiti D, Bakunts K, Reuveni M, Sanka SC, Martinez GM, Seftor EA, Meininger CJ, Wu G, Wesson DE, Hendrix MJC and Martinez-Zaguilan R. Vacuolar Type H+-ATPases at the plasma membrane regulate pH and cell migration in microvascular endothelial cells. J Cell Physiol, E-Pub, 2006.
Postovit LM, Seftor EA, Seftor REB and Hendrix MJC. Influence of the microenvironment on melanoma cell-fate determination and phenotype. Cancer Research, 66:432-436, 2006.
Postovit LM, Seftor EA, Seftor REB, Hendrix MJC. A Three-dimensional model to study the epigenetic effects induced by the microenvironment of human embryonic stem cells. Stem Cells, 24:501-505, 2006.
Norwood LE, Moss TJ, Margaryan NV, Cook SL, Wright L, Seftor EA, Hendrix MJ, Kirschmann DA, Wallrath LL. A requirement for dimerization of HP1Hsalpha in suppression of breast cancer invasion. J Biol Chem, 281:18668-18676, 2006.
Bailey CM, Khalkhali-Ellis Z, Seftor EA, Hendrix MJC. The biological functions of maspin. J Cell Physiol, in press, 2006.
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Emmet Hirsch, M.D.
Department of Obstetrics and Gynecology
M.D., Northwestern University
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Our laboratory primarily investigates infectious and inflammatory processes, with a special emphasis on the underpinnings of preterm labor. Premature birth is the major cause of neonatal morbidity and mortality in the developed world, accounting for at least 75% of neonatal deaths that are not due to congenital malformations. We hope to elucidate the processes by which intrauterine or systemic bacterial infections in pregnancy result in preterm delivery.
We work with both human and animal model systems to try to decipher the signaling pathways by which bacterial infections induce labor (infection is thought to be the cause of up to 30-40% of cases of unexplained preterm birth). Using mouse models and data and tissue samples obtained from pregnant women, members of the lab are investigating the roles of the uterus, fetus and placenta in this process. Ongoing work includes the use of mutant animals with altered expression of candidate critical factors (knockout and transgenic mice). A DNA microarray chip experiment is being used to characterize on a global scale the maternal and fetal signals important for preterm labor. This technology will help generate large and unique gene expression databases of laboring human and mouse pregnancy tissues.
Recent studies in our lab have focused on the roles of inflammatory mediators such as interleukin 1 (IL-1), tumor necrosis factor (TNF), prostaglandins and members of the innate immune system’s recognition pathway for bacterial pathogens (toll-like receptors - TLRs - and their downstream mediators). Data from the lab were the first to demonstrate that interleukin 1 is not an essential mediator of bacterially induced preterm labor, although it plays a necessary overlapping role together with TNF. Important distinctions between fetal and maternal gene expression have led to novel insights regarding the relative roles of the fetus and mother in initiating labor. Other studies have shown that the expression of prostaglandins (long considered the central downstream player in generating uterine contractions) is regulated via altered degradation rather than altered production. We have also demonstrated that TLR4 signaling is necessary for E. coli-induced preterm labor in the mouse. Ongoing in vivo and in vitro experiments explore the potential roles of other TLRs and of dominant-negative fusion proteins generated in the lab to interrupt the cascade leading from infection to expression of inflammatory markers, to expression of labor-specific genes, to delivery.
Recent Publications:
Hirsch E, Mehta SP, Blanchard RK. Differential fetal and maternal contributions to the
cytokine milieu in a murine model of infection-induced preterm birth. Am J Obstet Gynecol
(1999) 180(2 Pt 1): 429-434.
Irikura VM, Hirsch E, Hirsh D. Effects of interleukin 1 receptor antagonist
overexpression on infection by Listeria monocytogenes. Infect Immun (1999) 67: 1901-1909.
Mussalli GM, Blanchard RK, Brunnert SR, Hirsch E. Inflammatory cytokines in a murine
model of infection-induced preterm labor: Cause or effect? J Soc Gynecol Invest (1999)
6:188-195.
Muhle RA, Pavlidis P, Grundy WN, Hirsch E. A high throughput study of gene expression
in preterm labor with a subtractive microarray approach. Am J Obstet Gynecol (2001)
185:716-724.
Hirsch E, Wang H. The molecular pathophysiology of bacterially induced preterm labor: Insights from the murine model. J Soc Gynecol Investig. 2004 Apr;12(3):145-5.
Yoshimura K, Hirsch E, Kitano R, Kashimura M. Cervical varix accompanied by placenta previa in twin pregnancy. : J Obstet Gynaecol Res. 2004 Aug;30(4):323-5.
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Teresa H. Horton, Ph.D.
Department of Neurobiology and Physiology
Ph.D., University of Utah
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The ability to reproduce successfully requires that an organism coordinate gonadal function
with behavioral, physiological and environmental conditions conducive to the survival of
the resulting young. My primary research area investigates the mechanisms by which the
central nervous system integrates these multiple sources of information to regulate
reproductive function in mammals. The central focus of my research is the mechanism by
which secretion of the releasing hormone, gonadotropin releasing hormone (GnRH), from the
hypothalamus is regulated. GnRH controls the release of the gonadotropic hormones
(luteinizing hormone (LH) and follicle stimulating hormone (FSH)) from the anterior
pituitary; in turn, LH and FSH regulate the development of the gonads and germ cells. GnRH
has also been shown to function as a neurotransmitter to regulate reproductive behavior.
This dual function of GnRH facilitates the coordination of reproductive behavior with the
presence of mature gametes. The neurons that innervate the GnRH neurons form a complex
network providing for the integration of many forms of information. Thus the GnRH neurons
can be thought of as a nodal point in a complex information processing system. On going
research projects fall into three categories: 1) the role of the circadian system and
photoperiod in the regulation of GnRH secretion; 2) the mechanisms by which responses to
environmental and endocrine stimuli are altered during development and aging, and 3) the
mechanism by which seasonal changes in photoperiod regulate the ability of mammals to
release GnRH in response to other environmental stimuli, specifically pheromones from
potential mates. A wide variety of molecular biological, neurobiological,
endocrinological, and behavioral methods are used to study these problems.
Serum levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) in male
Siberian hamsters following exposure to a female (arrow). Males housed in short
photoperiod (SD controls) do not release LH upon exposure to a female, but males housed in
long days do (LD controls). The ability of a female to elicit release of LH from a male is
apparent after he has been returned to a long photoperiod for as few as four days (SD >
LD (4 days)) and is well developed after eleven days in long days (SD > LD (11 days)).
An increase in circulating FSH is stimulated by exposure to long photoperiods, but not by
exposure to a female. These data indicate that the secretion of LH and FSH are
differentially regulated by environmental factors. (Data from Anand, Olson, Turek, and
Horton, unpublished).
Recent References:
Bernard, D.J., I.Y. Merzlyak, T.H. Horton, and F.W. Turek. 2000. Differential
regulation of pituitary gonadotropin subunit messenger ribonucleic acid levels in
photostimulated Siberian hamsters. Biol. Reprod. 62: 155-161.
Miller BH, Olson SL, Turek FW, Levine JE, Horton TH, Takahashi JS. Circadian clock mutation disrupts estrous cyclicity and maintenance of pregnancy. Curr Biol. 2004 Aug 10;14(15):1367-73.
Anand S, Turek FW, Horton TH. Chemosensory stimulation of luteinizing hormone secretion in male Siberian hamsters (Phodopus sungorus). Biol Reprod. 2004 Apr;70(4):1033-40.
I also co-direct the Science and Engineering Research and Teaching Synthesis Program (SERTS). Click here to
visit the SERTS web site.
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Philip M. Iannaccone, MD, PhD
Department of Pediatrics
MD, SUNY Upstate Medical Center
PhD, University of Oxford (Lincoln Coll.) |
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In my early research career I established the clonal nature of chemically induced tumors. Later my lab established that exposure to direct acting mutagenic agents at preimplantation stages of development caused birth defects, poor implantation, greatly increased perinatal mortality and increased mortality throughout life. We established that endometrial cells had inducible phase I metabolizing activity, that TCDD was a powerful activator of AHH activity in endometrial cells and that estrogen inhibited TCDD's ability to induce this activity in these cells. We showed that the HPV genome was sufficient to induce tumorigenesis in transgenic mice. We established the nature of the embryonic lethality of null mutations in a gene that is now known as nodal and established its critical role in mesoderm formation.
We are currently working on two major projects. The first is designed to understand the role of the GLI family of transcription factors in normal development and disease. These genes code for proteins that reside in the cytoplasm but mediate the Sonic hedgehog signal transduction pathway following translocation to the nucleus. They regulate both cellular differentiation and proliferation. To fully understand the mechanism of their actions we have pursued and continue to study the genetic regulation of the genes at both transcriptional and post-transcriptional levels. We have established protein domains that are sufficient to regulate target genes and we are working to understand both co-activators in the process and biochemical mechanisms behind it. We very much want to pursue these mechanisms at a structural level. We have identified major downstream targets in a transcription factor dependent manner using high throughput gene expression profiling. We have shown that the protein Quaking binds the 3’UTR of the GLI1 RNA and represses translation of the GLI1 protein. The disruption of the pathway is associated with basal cell carcinoma of the skin, the most common cancer of man, prostate cancer, medullobalstoma and sarcomas. The pathway when under-active is associated with severe birth defects. In collaboration with Dave Walterhouse and Marilyn Lamm we have described the role of Sonic hedgehog and GLI in prostate development. Understanding the biochemical mechanisms behind the associations between the GLI family of genes and human disease could have a major public health impact.
The second project grew from work of my lab more than 20 years ago showing that chemically induced tumors were clonal in origin using mouse genetic chimeras. We developed new methodologies to establish that preneoplastic lesions were also clonal and thus the earliest events in carcinogenesis were stochastic and arose in single cells. This was done in rat chimeras where cell lineage could be established microscopically, a system that my lab developed. I observed that mosaic pattern within the tissues of these animals was prototypical and hence both conserved and regulated. Since these patterns were largely the result of cell division patterns we ascertained that they could be used to discern repetitive cell division rule sets in organ development. I went on to formally prove the patterns to be fractal, a prediction of repetitive cell division rules. My lab established computer models of this process and we continue to study the dynamics of cell division during organ development in this way. In an attempt to use increasingly robust markers of mosaic pattern some years ago we began to explore germ line modification of the rat. We continue to study somatic cell nuclear transfer in the rat, embryonic stem cells and the role of signaling pathways in the regulation of stem cell proliferation.
Recent Publications:
Iannaccone, P.M., Bader, M., and Galat, V. (2002). Cloning of rats. In "Principles of Cloning" (J. Cibelli, R. P. Lanza, K. H. S. Campbell, and M. D. West, Eds.), pp. 403-415. Academic Press, San Diego.
Zhou, Y., Galat, V., Garton, R., Taborn, G. and Iannaccone, P. Two-phase chemically defined culture system for preimplantation rat embryos. Genesis: J. of Genetics and Development 36:129-133, 2003.
Walterhouse, D., Lamm, M.L.G., Villavicencio, E., and Iannaccone, P.M. Emerging roles for Hedgehog-Patched- GLI signal transduction in reproduction. Biol. of Reprod. 69:8-14 (2003).
Yang, X.Z., Han, M-S., Niwa, K., and Iannaccone, P.M. Factors Required during Preculture of Rat Oocytes Soon after Sperm Penetration for Promoting Their Further Development in a Chemically Defined Medium. J. Repro. Devel. 50:533-40 (2004).
Lakzia, O., Frater, L., Yoo, Y., Villavicencio, E., Walterhouse, D.O., Goodwin, E.B. and Iannaccone, P.M.. STAR Proteins Quacking-6 and GLD-1 Regulate the Translation of Homologues GLI1 and Tra-1 Through a Conserved RNA 3'UTR Based Mechanism. Dev. Biol. 287:98-110. Epub 2005 Sep 29 (2005).
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J. Larry Jameson, M.D., Ph.D.
Department of Medicine
M.D., Ph.D., University of North Carolina
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Dr. Jameson’s laboratory focuses on nuclear receptor action and diseases associated with mutations in nuclear receptors. These projects currently involve three main areas: 1) Estrogen receptor (ER) signaling through tethered, or non-classical, pathways. Using selective ER mutations that cannot bind directly to DNA, we have shown that many of the actions of ER in breast, uterus, and ovary are mediated through transcriptional pathways that do not involve direct binding to a canonical estrogen response element (ERE). Using targeted mutagenesis, we have developed a mouse model to examine these pathways in vivo. 2) Role of orphan nuclear receptors, such as SF-1 and DAX-1, in gonadal dysgenesis. SF-1 and DAX-1 are involved in the development and function of several endocrine glands, including the adrenal, the gonads, and the ventromedial hypothalamus. We are using combination of analyses of human mutations, gene knockouts, and promoter mutagenesis studies to further define the functional role of SF-1 and DAX-1 in gonadal development. 3) Role of Sox-3 in germ cell development. We showed that targeted mutagenesis of Sox3 prevents male germ cell differentiation. We are currently exploring the molecular pathways regulated by Sox3, including the possibility that it functions as a tumor suppressor gene in germ cell tumors.
Recent Publications:
Lim HJ, Park HY, Ko YG, Lee SH, Cho SY, Lee EJ, Jameson JL, Jang Y. Dominant negative insulin-like growth factor-1 receptor inhibits neointimal formation through suppression of vascular smooth muscle cell migration and proliferation, and induction of apoptosis. Biochem Biophys Res Commun. 2004 Dec 17;325(3):1106-14.
Baum AE, Solberg LC, Kopp P, Ahmadiyeh N, Churchill G, Takahashi JS, Jameson JL, Redei EE. Quantitative Trait Loci Associated with Elevated TSH in the Wistar-Kyoto Rat. Endocrinology. [Epub 2004 Oct 28].
Ishikawa T, Lee EJ, Jameson JL. Nonhomologous end-joining ligation transfers DNA regulatory elements between cointroduced plasmids. Mol Cell Biol. 2004 Oct;24(19):8323-31.
Jameson JL. Citation for the 2004 Sidney H. Ingbar Distinguished Service Award of The Endocrine Society to Dr. Margaret A. Shupnik. Endocr Rev. 2004 Aug;25(4):686-7.
Raverot G, Lejeune H, Kotlar T, Pugeat M, Jameson JL. X-linked sex-determining region Y box 3 (SOX3) gene mutations are uncommon in men with idiopathic oligoazoospermic infertility. J Clin Endocrinol Metab. 2004 Aug;89(8):4146-8.
Jameson JL. Molecular mechanisms of end-organ resistance. Growth Horm IGF Res. 2004 Jun;14 Suppl A:S45-50.
Gehm BD, Levenson AS, Liu H, Lee EJ, Amundsen BM, Cushman M, Jordan VC, Jameson JL. Estrogenic effects of resveratrol in breast cancer cells expressing mutant and wild-type estrogen receptors: role of AF-1 and AF-2. J Steroid Biochem Mol Biol. 2004 Mar;88(3):223-34.
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Ralph R. Kazer, M.D.
Department of Obstetrics and Gynecology
M.D., Tufts University School of Medicine
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Dr. Kazer maintains an ongoing interest in gynecologic disorders associated with insulin
resistance and enhanced activity of insulin-like growth factor-I (IGF-I). Prior studies
from his unit describing abnormalities of the growth hormone-IGF-I axis in women with
polycystic ovary syndrome were followed by studies indicating that such abnormalities were
not dependent on abnormal serum concentrations of sex steroids. Most recently, in
conjunction with other investigators on the Chicago campus, he has been exploring the
potential role of IGF-I as a mediator of diet-associated breast cancer risk.
Recent Publications:
Kazer RR 1995 Insulin resistance, insulin-like growth factor I and breast cancer: a hypothesis. Int J Cancer 62:403-406.
Kazer RR 1996 Breast cancer and the reproductive endocrinologist. Fertil Steril 65:470-471.
Kazer RR. Endometrial biopsy should be abandoned as a routine component of the infertility evaluation. Fertil Steril. 2004 Nov;82(5):1297-8.
Confino E, Zhang X, Kazer RR. GnRHa flare and IVF pregnancy rates. Int J Gynaecol Obstet. 2004 Apr;85(1):36-9.
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Ji-Yong Julie Kim
Department of Obstetrics and Gynecology
Ph.D.,
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Our laboratory is interested in better understanding the dynamic interaction that occurs between the conceptus and the mother that allow for the establishment and maintenance of pregnancy. The major focus of our research is on the molecular events that occur in the endometrium in response to early embryonic signals and the invading trophoblast. Aberrant expression of genes in the endometrium during this time is detrimental to the maintenance of pregnancy and could lead to miscarriages, spontaneous abortions and infertility. In response to pregnancy hormones and conceptus factors, the endometrium undergoes a major transformation, termed decidualization. During this process, the stromal cells of the endometrium express important genes. We're focusing on the regulation of a major secretory product of the decidualizing stromal cells, insulin-like growth factor binding protein-1 (IGFBP-1). IGFBP-1 modulates the actions of insulin-like growth factors (IGFs) which are critical during early pregnancy and can act independently of IGFs to regulate trophoblast invasion. Recently, we demonstrated that two transcription factors, FKHR and HOXA10, which have been demonstrated to be important in reproductive processes, interact with one another and upregulate the IGFBP-1 promoter in a cooperative manner in endometrial stromal cells. Based on this novel data, studies have been designed to further delineate the mechanisms involved in the cooperative upregulation of the IGFBP-1 promoter by FKHR and HOXA10. With the use of a powerful new technique, chromatin immunoprecipitation (ChIP), the binding sites for endogenous FKHR and HOXA10 proteins on the endogenous IGFBP-1 gene within the chromatin in the decidualized stromal cells are determined. This technique allows one to study interaction of transcription factors with the chromatin as they occur in situ. Using this technique we will also look at FKHR and HOXA10 proteins in non-pregnant and pregnant endometrium in order to demonstrate the influence of the conceptus on FKHR and HOXA10 expression and their activation of the IGFBP-1 gene. Finally, we have found in the eutopic endometrium of cases of endometriosis that FKHR and HOXA10 do not significantly activate the IGFBP-1 promoter. It is apparent that stromal cells from the endometrium of endometriosis are obviously different from that of a normal endometrium. These studies will give a better understanding of the molecular events that may be associated with increased implantation failure in women with endometriosis. These results from these studies will provide valuable insights into the molecular dynamics of the endometrium in response to pregnancy.
Recent Publications:
Kim, J.J., Taylor, H.S., Akbas, G.E., Foucher, I., Trembleau, A., Jaffe, R.C., Fazleabas, A.T., Unterman, T.G. (2003) Regulation of insulin-like growth factor binding protein-1promoter activity by FKHR and HOXA10 in primate endometrial cells. Biology of Reproduction 68(1):24-30.
Arosh, J.A., Banu, S.K., Chapdelaine, P., Emond, V., Kim, J.J., MacLaren, L.A., Fortier MA. (2003) Molecular Cloning and Characterization of Bovine Prostaglandin E(2) Receptors EP2 and EP4: Expression and Regulation in Endometrium and Myometrium during the Estrous Cycle and Early Pregnancy. Endocrinology 144(7):3076-3091.
Fazleabas, A.T., Kim, J.J. (2003) What makes an embryo stick?. Science 299:355-356.
Fazleabas, A.T., Kim, J.J. and Strakova, Z. (2004) Implantation: Embryonic signals and the modulation of the uterine environment. Placenta. 25 Suppl:S26-31.
Jasinska, A., Han, V., Fazleabas, A.T., Kim, J.J. (2004) Induction of Insulin-like growth factor-binding protein-1 in baboon endometrial stromal cells by cells of embryonic origin. J Soc Gyn Investig 11(6):399-405.
Kim J.J., Fazleabas, A.T. (2004) Uterine receptivity and implantation: The regulation and action of insulin-like growth factor binding protein-1 (IGFBP-1), HOXA10 and forkhead transcription factor-1 (FOXO-1) in the baboon endometrium. Reprod Biol Endocrinol. 2:34-39.
Fazleabas AT, Strakova Z, Kim JJ. Implantation in the baboon. Gynecol Obstet Invest. 2004;57(1):30-1.
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Chris Kuzawa, Ph.D., MsPH
Department of Anthropology
Ph.D., Emory University
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As a biological anthropologist with training in public health and epidemiology, my research evaluates the long-term impact of early life developmental processes, with a primary focus on the role that the intrauterine and early postnatal environments have on adult health. The premise of this research, supported by studies in both human populations and animal models, is that what a mother eats during pregnancy, her access to adequate prenatal care, or her level of stress, may permanently alter offspring biology in a fashion that influences risk for the most common causes of adult suffering and mortality, including hypertension, diabetes, and heart attacks. This perspective may have particular relevance for understanding health patterns in populations experiencing rapid nutritional and lifestyle change, as individuals undernourished early in life who grow up to experience relative nutritional abundance as adults may be at greatest risk. I and my colleagues are investigating these questions in the Philippines, a population currently experiencing changes in culture, lifestyle and health. Our research shows that poor maternal/fetal nutrition and growth predict elevated blood pressure, a more atherogenic lipid profile, and an attenuated capacity to mount an immune response in adolescence and early adulthood. A second theme in my work focuses on the use of evolutionary principles to understand the pattern of human growth and development, the characteristics of the human life cycle, and the determinants of health and disease.
Recent Publications:
Kuzawa CW, The fetal origins of developmental plasticity. Are maternal cues reliable predictors of future nutritional environments? Amer J Hum Biol (in press)
Kuzawa CW and IL Pike, The fetal origins of developmental plasticity. Introduction to the special issue. Amer J Hum Biol (in press)
Kuzawa CW and LS Adair (2004), A supply-demand model of fetal energy sufficiency predicts lipid profiles in male but not female adolescent Filipinos. Eur J Clin Nutr, 58(3) 438-48.
McDade, TW, Kuzawa, CW, Adair, LS, and M Beck (2004), Prenatal and early postnatal environments are significant predictors of total immunoglobulin E concentration in Filipino adolescents. Clin Exp Allergy, 34 (1) p.44-50.
Kuzawa CW (2004), Modeling fetal adaptation to nutrient restriction: testing the fetal origins hypothesis with a supply-demand model. J Nutrition, 134: 194-200.
Leonard WR, Robertson ML, Snodgrass JJ, Kuzawa CW (2003), Metabolic correlates of hominid brain evolution. Comp Biochem Physiol A Mol Integr Physiol. 136(1):5-15.
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Chung Lee, Ph.D.
Department of Irology
Ph.D., West Virginia University
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My research has been in the area of prostatic physiology and cell biology. The prostate has
many unique properties which make it an interesting subject for scientific investigation.
For example, since the prostate is an androgen-sensitive tissue, maintenance of its
structural and functional integrity requires a constant support of androgen in the
circulation. Depletion of this androgenic support, as by castration in the host, would
result in drastic metabolic changes leading to programmed cell death and tissue
involution. In this regard, the prostate can be used to study the mechanism of androgen
action and the biology of programmed cell death. Furthermore, the prostate is also
susceptible to the development of abnormal growth, resulting in benign prostatic
hyperplasia and carcinoma of the prostate. Therefore, understanding the biology of
carcinogenesis and growth regulation in the prostate is an important health concern.
Finally, the prostate is a complex ductal system with branches and sub-branches extending
from one end to the other. The recent recognition of a regional variation in structural
and functional activity along the ductal system has made it possible for us to study the
various mechanisms that regulate the changing cellular activities in various regions of
the prostate. Again, this aspect of prostatic biology offers additional opportunity for
in-depth investigation in cellular and molecular biology. Currently, we are actively
pursuing the following subjects:
Characterization of prostatic ductal system as it relates to cellular proliferation, differentiation, and degeneration.
Characterization of the biological events associated with programmed cell death during the course of castration-induced prostatic involution.
Stromal and epithelial interaction in the prostate as it relates to cellular differentiation and proliferation and to the mechanism of androgen action.
Role of growth factors in mass growth of normal and malignant prostatic epithelial cells as it relates to therapy of prostatic cancer.
Recent Publications:
Zhang L, Shi J, Feng J, Klocker H, Lee C, Zhang J. Type IV collagenase (matrix metalloproteinase-2 and -9) in prostate cancer. 1: Prostate Cancer Prostatic Dis. 2004;7(4):327-32.
Pins MR, Fiadjoe JE, Korley F, Wong M, Rademaker AW, Jovanovic B, Yoo TK, Kozlowski JM, Raji A, Yang XJ, Lee C. Clusterin as a possible predictor for biochemical recurrence of prostate cancer following radical prostatectomy with intermediate Gleason scores: a preliminary report. Prostate Cancer Prostatic Dis. 2004;7(3):243-8.
Shim JH, Danielpour D, Lee C, Kim YS, Bahk YY, Yoo TK. Proteome profile changes during transdifferentiation of NRP-152 rat prostatic basal epithelial cells. Mol Cells. 2004 Feb 29;17(1):108-16.
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Jon E. Levine, Ph.D.
Department of Neurobiology and Physiology
Ph.D., University of Illinois
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We are particularly interested in the activity of neurons that synthesize and release
luteinizing hormone-releasing hormone (LHRH), a decapeptide that mediates hypothalamic
regulation of pituitary gonadotropes, thereby controlling ovulatory cycles and other
critical reproductive functions. Our studies also focus on other important neuromodulators
of reproductive function, such as neuropeptideY (NPY). To study the activity of these and
other peptidergic cell groups, we use in vivo microdialysisas well as in vitro
superfusion of tissue and cell cultures to measure the ongoing release of
peptideregulators under various physiological and pharmacological conditions. In situ
hybridization andrelated molecular technologies are also used to analyze the physiological
regulation of gene expression in these neurons. Three basic aspects of hypothalamic
neuropeptide function are examined: the intrinsic cellular activities of these systems
(e.g., mechanisms regulating pulsatile release patterns), the regulation of pituitary
hormone secretion by hypothalamic peptidergic neurons, and the regulation of peptide
neurosecretion and gene expression by hypothalamic neurotransmitters and gonadal steroid
feedback mechanisms. Integrated studies at these three levels are directed at
understanding basic reproductive processes, such as the generation of preovulatory
gonadotropin surges. A midcycle surge of gonadotropins provides the endocrine trigger for
ovulation in virtually all mammals and is dependent upon the sufficient and appropriate
release of LHRH and other hypothalamic regulators, such as NPY. We are therefore
attempting to gain a detailed understanding of the cellular mechanisms governing
thesynthesis, release, and actions of these peptides throughout this critical
periovulatory period. In other related studies, the participation of LHRH, NPY, and other
peptidergic cell groups in homeostaticgonadal feedback mechanisms and photoperiodic
regulation of the reproductive axis are also being examined. A long-term goal of this
laboratory is to understand how these neuropeptidergic systems can coordinate several
neural and endocrine activities to produce an appropriate homeostatic state, such as
reproductive competency. It is also hoped that our studies may ultimately provide useful
information in the treatment of some forms of infertility and in the development of new
contraceptive strategies.
Recent Publications:
Miller BH, Olson SL, Turek FW, Levine JE, Horton TH, Takahashi JS. Circadian clock mutation disrupts estrous cyclicity and maintenance of pregnancy. Curr Biol. 2004 Aug 10;14(15):1367-73.
Szeto A, Gonzales JA, Spitzer SB, Levine JE, Zaias J, Saab PG, Schneiderman N, McCabe PM. Circulating levels of glucocorticoid hormones in WHHL and NZW rabbits: circadian cycle and response to repeated social encounter. Psychoneuroendocrinology. 2004 Aug;29(7):861-6.
Froment P, Staub C, Hembert S, Pisselet C, Magistrini M, Delaleu B, Seurin D, Levine JE, Johnson L, Binoux M, Monget P. Reproductive abnormalities in human insulin-like growth factor-binding protein-1 transgenic male mice. Endocrinology. 2004 Apr;145(4):2080-91.
Hill JW, Urban JH, Xu M, Levine JE. Estrogen Induces Neuropeptide Y (NPY) Y1 receptor gene expression and responsiveness to NPY in gonadotrope-enriched pituitary cell cultures. Endocrinology. 2004 May;145(5):2283-90.
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Daniel I.H. Linzer, Ph.D.
Department of Biochemistry, Molecular Biology, and Cell Biology
Ph.D., Princeton University
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The placenta mediates implantation of the embryo into the maternal uterus; it forms a barrier
to the maternal immune system and to the passage of certain compounds into the fetus; it
provides a vascular system for the exchange of nutrients and waste products between the
mother and the fetus; and it synthesizes hormones that act on the mother, the fetus, and
the placenta. In many mammalian species, hormones closely related to prolactin are
produced by the placenta. In the mouse, these placental proteins include placental
lactogen I, placental lactogen II, proliferin, and proliferin-related protein. Placental
lactogens I and II each bind to the prolactin receptor. During early pregnancy, prolactin
is the principal hormone that binds to the prolactin receptor, but at mid-pregnancy
prolactin levels decline and placental lactogen I appears at high levels; later in
pregnancy, placental lactogen I is replaced in the circulation by placental lactogen II.
We are studying the placental- and temporal-specific synthesis of these hormones as a
means of following trophoblast differentiation and placental development. Another area of
study is the expression and signal transducing action of the prolactin receptor, the
target of these hormones.
We have recently demonstrated that proliferin stimulates angiogenesis, whereas proliferin-related protein
inhibits this process. Proliferin, which is secreted earlier in pregnancy than
proliferin-related protein, may be responsible for stimulating the migration of blood
vessels in the uterus towards the placenta. Proliferin-related protein may then prevent
the reestablishment of intact vessels, enabling the placental trophoblast cells to come
into direct contact with maternal blood. It is also possible that proliferin-related
protein restricts blood vessel growth, thereby limiting the growth and invasiveness of the
placenta. Current efforts are directed at understanding the molecular mechanisms by which
these hormones act.
Recent Publications:
Thadani PV, Strauss JF 3rd, Dey SK, Anderson VM, Audus KL, Coats KS, Cross JC, Erlebacher A, Ganapathy V, Linzer DI, Miller RK, Novak DA, Rapaka RS, Sadovsky Y, Salafia CM, Soares M, Unadkat J. National Institute on Drug Abuse Conference report on placental proteins, drug transport, and fetal development.Am J Obstet Gynecol. 2004 Dec;191(6):1858-62. Review.
Zhou B, Kong X, Linzer DI. Enhanced Recovery from Thrombocytopenia and Neutropenia in Mice Constitutively Expressing a Placental Hematopoietic Cytokine. Endocrinology. [Epub 2004 Sep 16]
Soloveva V, Linzer DI. Differentiation of placental trophoblast giant cells requires downregulation of p53 and Rb. Placenta. 2004 Jan;25(1):29-36.
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Kelly E. Mayo, Ph.D.
Department of Biochemistry, Molecular
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Our laboratory investigates cell signaling and gene expression in the mammalian reproductive axis.
Our research program in reproductive biology seeks to understand how hormones secreted from the pituitary gland (FSH and LH) act on the ovary to bring about the changes in cell proliferation, cell differentiation and gene expression that will result in ovulation and luteinization of the ovarian follicle during each reproductive cycle. We use the genes encoding the hormones inhibin and activin, which are produced in the ovary and act on the pituitary gland to regulate reproductive hormone secretion, as a model system to address these questions. We are presently focused on two major research directions. We are investigating the dynamic regulation of inhibin expression during the reproductive cycle, and are exploring the roles of cAMP-responsive transcription factors (CREB and ICER) as well as the related orphan nuclear receptors steroidogenic factor-1 (SF-1) and liver receptor homologue-1 (LRH-1), in this process. We are also investigating developmental pathways in the ovary involved in the initial formation and growth of ovarian follicles, and are attempting to understand how inhibin and activin regulate normal follicle development and how their misexpression might contribute to the formation of abnormal follicles. Our work focuses on molecular mechanisms regulating normal reproductive function, but is substantially informed by, and relevant to, reproductive disorders that impact fertility.
Recent Publications:
Chen, W., Woodruff, T.K. and Mayo, K.E. (2000). Activin A-Induced HepG2 Liver Cell Apoptosis Involvement of Activin Receptors and Smad Proteins. Endocrinology 141:1263-125.
Horikawa M, Kirkman NJ, Mayo KE, Mulders SM, Zhou J, Bondy CA, Hsu SY, King GJ, Adashi EY. The Mouse Germ-Cell-Specific Leucine-Rich Repeat Protein NALP14: A Member of the NACHT Nucleoside Triphosphatase Family. Biol Reprod. [Epub 2004 Dec 8].
Ahn JM, Jung HK, Cho C, Choi D, Mayo KE, Cho BN. Changes in the reproductive functions of mice due to injection of a Plasmid expressing an inhibin alpha-subunit into muscle: a transient transgenic model. Mol Cells. 2004 Aug 31;18(1):79-86.
Seok OS, Ahn JM, Mayo KE, Cho BN. Developmental changes in inhibin-alpha gene expression in the mouse testis. Mol Cells. 2004 Feb 29;17(1):67-72.
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Thomas W. McDade, Ph.D.
Department of Anthropology
Ph.D. Emory University, Atlanta, Georgia
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The Laboratory for Human Biology Research is located within the Anthropology Department, and supports a range of projects investigating issues related to human health, growth and development, stress, reproductive ecology, energetics, and body composition. Current projects involve research in Samoa, Kenya, Bolivia, Siberia, and the Philippines. A primary mission of the laboratory is the development of minimally invasive, "field-friendly" methods for assessing biomarkers of health and development that can be used to facilitate population-level research in remote field settings. In recent research, whole blood samples have been collected from finger sticks and dried on filter paper in the field, and then brought back to the laboratory for analysis using modified ELISA protocols. Analysis of saliva and urine samples is also supported. The laboratory is committed to using these methods to facilitate collaborative, population-based research into the relationships between humans and their environments around the world.
Recent Publications:
McDade, T.W. (in press). Parent-offspring conflict and the cultural ecology of breastfeeding. Human Nature.
McDade, T.W., Stallings, J.F., Angold, A., Costello, E.J., Burleson, M., Cacioppo, J.T., Glaser, R. and C.M. Worthman (2000). Epstein-Barr virus antibodies in whole blood spots: A minimally-invasive method for assessing cell-mediated immunity. Psychosomatic Medicine 62: 560-568.
McDade, T.W., Stallings, J.F. and C.M. Worthman (2000). Culture change and stress in Western Samoan youth: Methodological issues in the cross-cultural study of stress and immune function. American Journal of Human Biology 12: 792-802.
McDade TW, Burhop J, Dohnal J. High-sensitivity enzyme immunoassay for C-reactive protein in dried blood spots. Clin Chem. 2004 Mar;50(3):652-4.
McDade TW, Kuzawa CW, Adair LS, Beck MA. Prenatal and early postnatal environments are significant predictors of total immunoglobulin E concentration in Filipino adolescents. Clin Exp Allergy. 2004 Jan;34(1):44-50.
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Kevin E. McKenna, Ph.D.
Department of Physiology and Urology
Ph.D., Johns Hopkins School of Medicine
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My
research focuses on the spinal cord control of autonomic function, with a particular
interest in the neural control of sexual function. This research involves an integrated
approach, using modern neuroanatomical, neurophysiological, biochemical and
pharmacological techniques.
Specific projects include:
- Identification of the somatic and autonomic afferents and efferents innervating pelvic organs, using retrograde tracing techniques.
- Study of the mechanisms of sexual reflexes in both male and female rats using a novel preparation.
- Analysis of the descending control of sexual function using physiological, pharmacological and anatomical techniques.
- Study of the neural control of prostatic secretion and prostatic growth using physiological, pharmacological, anatomical, and biochemical techniques.
- Analysis of the mechanisms of diabetic impotence.
Selected Publications:
McVary KT, Rathnau CH,
McKenna KE 1996 Sexual dysfunction in the diabetic BB/WOR rat: A role of central
neuropathy. American Journal of Physiology (in press).
McKenna KE, Marson L 1996
CNS cell groups involved in the control of the ischiocavernosus and bulbospongiosus
muscles: A transneuronal tracing study using pseudorabies virus. Journal of Comparative
Neurology (in press).
Coolen LM, Allard J, Truitt WA, McKenna KE. Central regulation of ejaculation. Physiol Behav. 2004 Nov 15;83(2):203-15.
McVary KT, McKenna KE. The relationship between erectile dysfunction and lower urinary tract symptoms: epidemiological, clinical, and basic science evidence. Curr Urol Rep. 2004 Aug;5(4):251-7.
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Magdy P. Milad, M.D.
Department of Obstetrics and Gynecology
M.D., Wayne State University
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My basic science research activities investigates the progesterone receptor located on the
head of spermatozoa. Progesterone induces the acrosome reaction by causing calcium influx
presumably at the progesterone receptor.
However, this membrane
bound receptor has not been well characterized. Some immunosuppressant drugs have been
found to interact with progesterone receptor chaperone proteins and attenuate progesterone
mediated transcription in some cell systems. Preliminary results suggest that FK506, an
immunosuppressant drug, does induce the sperm acrosome reaction independent of the
presence of progesterone. This may have important implications for facilitating in vitro
fertilization of human oocytes and may have far reaching implications for contraception.
Stress has long been
implicated in adverse pregnancy outcome although the literature in this regard is somewhat
lacking. My clinical research involves measuring markers of stress and correlating these
results with pregnancy outcome among patients undergoing IVF. This study will quantitate
stress levels using biochemical and subjective tests in patients who have achieved
pregnancy while undergoing assisted reproduction.
Recent Publications:
Dragisic KG, Milad MP. Sexual functioning and patient expectations of sexual functioning after hysterectomy. Am J Obstet Gynecol. 2004 May;190(5):1416-8.
Grube JO, Milad MP, Damme-Sorenen J. Preemptive analgesia does not reduce pain or improve postoperative functioning. JSLS. 2004 Jan-Mar;8(1):15-8.
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