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.
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