Ultrashortloop Feedback on GnRH Biosynthesis

摘要：促性腺激素释放激素(GnRH)是哺乳动物生殖功能和行为的中枢调节因子。它从下丘脑分泌，诱导促性腺激素释放，进而刺激性腺功能；排卵前GnRH释放激增，与性接受期一致，在诱导排卵时达到顶峰。初步结果表明，促性腺激素释放激素的代谢产物(S)可能调节其生物合成，并诱导大鼠性行为。这些结果导致了GnRH过度增长的假说，即GnRH在GnRH激增与性行为的开始同步中起着重要作用。这一建议将通过确定代谢物调节促性腺激素释放激素生物合成的潜在机制来解决这一假说的一个方面(S)。为了确定(1)以GT1-7细胞作为体外模型发挥生物学作用所需的促性腺激素释放激素代谢产物(S)；(2)促性腺激素释放激素代谢产物(S)参与调节大鼠(体内)促性腺激素释放激素基因表达；(3)促性腺激素释放激素代谢产物(S)调节促性腺激素释放激素基因表达的机制。总的来说，这些研究将使用生化和分子生物学方法进行分析。本研究的结果有望鉴定出促性腺激素释放激素的活性代谢物(S)，并确定该代谢物(S)调节促性腺激素释放激素基因表达的机制。这是第一次将GnRH代谢产物对GnRH基因表达的直接生物学效应归因于此的研究。这一建议的成功完成将进一步澄清我们对哺乳动物生殖功能的中央调节的理解，并将为未来的研究铺平道路，以确定内分泌系统与排卵前行为汇聚的潜在机制。预计该项目将为博士后、研究生以及大学生和/或高中生提供科学培训。

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.