This application seeks funding for a Chicago Center for Reproductive Research (U54). The Center will consist of four projects and three cores and will carry out multidisciplinary investigations of steroid hormone, gonadotropin, and insulin signaling pathways in the reproductive axis. Project 1, the clinical research project, will determine the role of a variant steroidogenic enzyme 17beta-hydroxysteroid dehydrogenase type 5 (17beta-HSD5), the major enzyme responsible for ovarian testosterone production, in the polycystic ovary syndrome (PCOS). Ovarian testosterone secretion in response to in vivo manipulation of luteinizing hormone (LH) and insulin levels will be related to 17beta-HSD5 genotype and may provide the first direct evidence for a PCOS phenotype resulting from a specific genetic trait. Project 2 will aim to determine the mechanism of estrogen regulation in the central reproductive axis in cell lines and transgenic mice using a series of estrogen receptor (ER) mutants and knockout (KO) mice. Mice bearing a conditional knock-out of ER-alpha and/or ER-beta in either the gonadotropin releasing hormone (GnRH) neuron or gonadotrope will determine the mechanism of negative feedback control by estrogen. Project 3, closely complementing Project 2, will test the hypothesis that progesterone receptors (PRs) mediate the inhibitory effects of progesterone on the GnRH neuron, and determine the anatomic locations of PRs involved in this regulatory mechanism. Specific experiments are planned to determine whether GnRH neurons express PRs and mediate inhibition of GnRH pulsatility. Project 4 aims to determine the importance of insulin regulation in the development and expression of gonadotrope-specific genes.
The aims will use conditional s of the insulin receptor and the cAMP response element (CREB) binding protein (CBP) as well as explore the role of insulin signaling in CBP recruitment to the transcription complex. The Molecular Technology Core, will provide investigators with timely acquisition of DNA sequence and performance of routine and/or specialized molecular biology procedures, the reagents for production of transgenic and mice and the histological analysis of the mouse lines they construct. The Ligand Assay Core, will provide hormone assays for studies involving human subjects and animal models. The proposed Chicago Center for Reproductive Research will also utilize existing cores at the University of Chicago and Northwestern University. The NIH-funded General Clinical Research Center (GCRC) at the University of Chicago, where Dr. Robert L. Rosenfield is Associate Program Director, will also be an important resource for Center participants. It is anticipated that the research performed under this Center will lead to an increased understanding of signaling pathways in reproduction.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD041859-05
Application #
7030932
Study Section
Special Emphasis Panel (ZHD1-DRG-D (23))
Program Officer
Rankin, Tracy L
Project Start
2003-04-28
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
5
Fiscal Year
2006
Total Cost
$1,422,799
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Rosenfield, Robert L (2015) The Polycystic Ovary Morphology-Polycystic Ovary Syndrome Spectrum. J Pediatr Adolesc Gynecol 28:412-9
Avtanski, Dimiter; Novaira, Horacio J; Wu, Sheng et al. (2014) Both estrogen receptor ? and ? stimulate pituitary GH gene expression. Mol Endocrinol 28:40-52
Na, Giyoun; Wolfe, Andrew; Ko, Chemyong et al. (2013) A low-copy-number plasmid for retrieval of toxic genes from BACs and generation of conditional targeting constructs. Mol Biotechnol 54:504-14
Rosenfield, Robert L; Wroblewski, Kristen; Padmanabhan, Vasantha et al. (2012) Antimüllerian hormone levels are independently related to ovarian hyperandrogenism and polycystic ovaries. Fertil Steril 98:242-9
Raivio, Taneli; Avbelj, Magdalena; McCabe, Mark J et al. (2012) Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia. J Clin Endocrinol Metab 97:E694-9
Wu, Sheng; Divall, Sara; Wondisford, Fredric et al. (2012) Reproductive tissues maintain insulin sensitivity in diet-induced obesity. Diabetes 61:114-23
Diaczok, Daniel; DiVall, Sara; Matsuo, Isao et al. (2011) Deletion of Otx2 in GnRH neurons results in a mouse model of hypogonadotropic hypogonadism. Mol Endocrinol 25:833-46
Novaira, Horacio J; Yates, Melissa; Diaczok, Daniel et al. (2011) The gonadotropin-releasing hormone cell-specific element is required for normal puberty and estrous cyclicity. J Neurosci 31:3336-43
Wu, Sheng; Divall, Sara; Hoffman, Gloria E et al. (2011) Jak2 is necessary for neuroendocrine control of female reproduction. J Neurosci 31:184-92
Qin, Kenan; Rosenfield, Robert L (2011) Mutations of the hexose-6-phosphate dehydrogenase gene rarely cause hyperandrogenemic polycystic ovary syndrome. Steroids 76:135-9

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