Kisspeptin/GPR54 in the Female Neuroendocrine Axis

描述(申请人提供)：KiSS-1基因编码一个名为KISS-Peptins的多肽家族，该家族与G蛋白偶联受体Gpr54结合。KiSS-1和Gpr54在前脑中表达，Gpr54基因的突变会导致人类和小鼠的低促性腺激素减退。KiSspeptins刺激促性腺激素释放激素(GnRH)和促性腺激素(FSH)的分泌，KISS-1基因受性腺类固醇调节--表明KISS-1信号通过GPR54在生殖的神经内分泌调节中发挥作用。这项研究的总体目标是了解Kispeptins在雌性大鼠和小鼠促性腺激素分泌调节中的生理功能。我们的第一个目标是评估Kispeptins在排卵前促性腺激素激增中的作用。在这里，我们将测试kisspeptin/Gpr54mRNA信号通路是否在雌激素(E)/孕酮(P)诱导的促黄体生成素(LH)峰的产生中起关键作用。我们还将评估前腹侧脑室周围核(AVPV)的KiSS-1神经元介导来自视交叉上核(SCN)的E、P和昼夜节律信号对LH峰产生的影响的可能性。第二个目的是研究Kispeptins在青春期的开始和黄体生成素激增机制的性别分化中的作用。在这些实验中，我们将评估Kispeptin神经元在性发育过程中的变化，并确定这些变化是否依赖于性类固醇。我们还将调查青春期是否与Kispeptins刺激GnRH神经元活动的能力增加有关。此外，我们将通过评估将功能性GPr54基因导入GnRH神经元的效果来确定GnRH神经元中的Kisspeptin/Gpr54信号是否在青春期起关键作用。最后，我们将调查KiSS-1和GPR54表达的性别差异是否与新生儿关键期的组织过程或青春期激素依赖的激活事件有关。阐明Kispeptins在女性促性腺激素分泌的发育和调节中的作用，可能会提高我们对人类特发性性腺激素低促性腺功能减退症的理解，并可能为改进治疗早熟或延迟青春期和不孕症的治疗提供科学依据。也可以想象，这些知识可以作为开发新的和更好的荷尔蒙避孕策略的基础。

DESCRIPTION (provided by applicant): The KiSS-1 gene codes for a family of peptides called kisspeptins, which bind to a G protein-coupled receptor known as GPR54. KiSS-1 and GPR54 are expressed in the forebrain, and mutations in the GPR54 gene cause hypogonadotropic hypogonadism in humans and mice. Kisspeptins stimulate gonadotropin- releasing hormone (GnRH) and gonadotropin (LH and FSH) secretion, and the KiSS-1 gene is regulated by gonadal steroids-suggesting that kisspeptin signaling through GPR54 plays a role in the neuroendocrine regulation of reproduction. The overall goal of this research is to understand the physiological function of kisspeptins in the regulation of gonadotropin secretion in the female rat and mouse. Our first objective is to assess the role of kisspeptins in the preovulatory gonadotropin surge. Here, we will test whether kisspeptin/ GPR54 mRNA signaling pathway is critical for the generation an estrogen (E)/progesterone (P)-induced LH surge. We will also evaluate the possibility that KiSS-1 neurons of the anteroventral periventricular nucleus (AVPV) mediate the effects of E, P, and circadian signals from the suprachiasmatic nucleus (SCN) on the generation of LH surges. The second objective is to investigate the role of kisspeptins in the onset of puberty and sexual differentiation of the LH surge mechanism. In these experiments, we will evaluate changes in kisspeptin neurons over sexual development and determine whether these changes are dependent on sex steroids. We will also investigate whether puberty is associated with an increase in the ability of kisspeptins to stimulate the activity of GnRH neurons. In addition, we will determine whether kisspeptin/GPR54 signaling in GnRH neurons plays a critical role in puberty by evaluating the effects of introducing a functional GPR54 gene into GnRH neurons of GPR54 KOs. Finally, we will investigate whether sex differences in the expression of KiSS-1 and GPR54 are attributable to organizational processes that during the neonatal critical period or hormone-dependent activational events at puberty. Elucidating the role of kisspeptins in the development and regulation of gonadotropin secretion in females may improve our understanding of idiopathic hypogonadotropic hypogonadism in humans and could provide the scientific rationale for improved therapies to treat precocious or delayed puberty and infertility. It's also conceivable that this knowledge could serve as the basis for the development of new and better strategies for hormonal contraception.