Ultrashortloop Feedback on GnRH Biosynthesis

摘要：十肽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。它由下丘脑分泌，诱导促性腺激素的释放，进而刺激性腺功能；排卵前GnRH释放的激增，与性接受期相吻合，在诱导排卵时达到高潮。初步结果表明，GnRH的代谢产物可能调节其生物合成并诱导大鼠的性行为。这些结果导致了GnRH在同步GnRH激增与性行为开始的重要假设。本提案将通过确定代谢物调节GnRH生物合成的机制来解决这一假设的一个方面。我们提出了三个具体目标来确定(1)以GT1-7细胞系为体外模型，发挥生物作用所需的GnRH代谢物；(2) GnRH代谢物参与调节大鼠（体内）GnRH基因表达；(3) GnRH代谢物调控GnRH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。预计本提案的结果将确定活性GnRH代谢物，并确定代谢物调节GnRH基因表达的机制。这是首次将GnRH代谢产物对GnRH基因表达的直接生物学效应归因于研究。这项研究的成功完成将进一步阐明我们对哺乳动物生殖功能中枢调控的认识，并为未来研究确定内分泌系统与排卵前行为趋同的机制铺平道路。预计该项目将为博士后、研究生和大中专学生提供科学培训。

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.