The specialized Reproductive Sciences Research Center described in this proposal is comprised of four research projects and two core facilities that will perform research designed to achieve a broad understanding of the testes and their two major projects, germ cells and steroid hormones. The goals of the Center and those of each component project are firmly based on the Research Objectives as stated in RFA HD-95-017. The role of germease, a recently identified testicular protease, in mediating the migration of germ cells through the seminiferous epithelium will significantly add to the literature on this cascade of events involving testicular proteases, protease inhibitors and junctional proteins. The determination of the molecular events in the regulation of gene expression by androgen and other reproductive hormones in vivo will provide a better understanding of the mechanism of action of reproductive hormones and the DNA elements and nuclear proteins that interact to produce tissue- and cell-specificity and hormone responsiveness. The discovery that specific members of the GATA family of Transcription factors are expressed in the testis and that they regulate testicular gene expression will be expanded into a comprehensive analysis of the interaction of GTA factors, especially GATA-1 and GATA-4, with the inhibin/activins genes in testicular cells. Whether germ cell development is mediated in part by the apoptotic pathway controlled by the bcl-2 gene family will be tested by analyzing the regulation of the expression of bcl-x in specific germ cells and the ability of Bcl-x protein isoforms to influence germ cell survival. An emerging them in transcriptional regulation by nuclear receptors in response to multiple hormonal signals is the concept of transcriptional interference among receptors in this superfamily. The cofactors that are the targets of this interference play an important role in transcriptional activation by sex steroids. Transcriptional interference between the progesterone receptor (PR) and thyroid hormone receptor will be used to identify and functionally characterize a coactivator(s) of PR-mediated transactivation. Each of the projects in the Center has responded to opportunities presented by previous research progress and by new data to advance the fields of sex steroid action or testicular regulation. The core laboratories are continuations of well-established facilities that have each reacted to changes in the Center Program to most efficiently meet Project needs.
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