Ultrashortloop Feedback on GnRH Biosynthesis

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Abstract: The decapeptide gonadotropin-releasing hormone (GnRH) is the central regulator of reproductive function and behavior in mammals. It is secreted from the hypothalamus to induce the release of gonadotropins, which in turn stimulate gonadal function; a preovulatory surge of GnRH release, which coincides with a period of sexual receptivity, culminates in the induction of ovulation. Preliminary results suggest that a metabolic product(s) of GnRH may regulate its biosynthesis as well as induce sexual behavior in the rat. These results lead to the overaching hypothesis that GnRH is important in synchronizing the GnRH surge with the initiation of sexual behavior. This proposal will address one aspect of this hypothesis by determining the mechanism underlying the regulation of GnRH biosynthesis by the metabolite(s). Three specific aims are proposed to determine (1) the GnRH metabolite(s) required to exert a biological action using the GT1-7 cell line as the in vitro model; (2) the involvement of GnRH metabolite(s) in regulating GnRH gene expression in the rat (in vivo); and, (3) the mechanism through which GnRH metabolite(s) regulates GnRH gene expression. Collectively, these studies will use biochemical and molecular biological methods for analysis. It is expected that the results of this proposal will identify the active GnRH metabolite(s) and determine the mechanism by which the metabolite(s) may regulate GnRH gene expression. This is the first study to ascribe a direct biological effect of a metabolic product of GnRH on GnRH gene expression. Successful completion of this proposal will further clarify our understanding of the central regulation of reproductive function in mammals and will pave the way for future studies to determine the mechanism underlying the convergence of the endocrine system with behavior during the preovulatory period. It is anticipated that this project will provide scientific training for a postdoctoral fellow, a graduate student, and college and/or high school students.