Kisspeptin/GPR54 in the Female Neuroendocrine Axis

描述（由申请人提供）：KiSS-1基因编码一个被称为kisspeptin的肽家族，它与被称为GPR54的G蛋白偶联受体结合。KiSS-1和GPR54在前脑表达，GPR54基因突变导致人类和小鼠的促性腺功能减退。kisspeptin刺激促性腺激素释放激素（GnRH）和促性腺激素（LH和FSH）的分泌，KiSS-1基因受到性腺激素的调控，提示kisspeptin通过GPR54信号通路参与生殖神经内分泌调节。本研究的总体目标是了解kisspeptin在雌性大鼠和小鼠中调节促性腺激素分泌的生理功能。我们的第一个目标是评估kisspeptin在排卵前促性腺激素激增中的作用。在这里，我们将测试kisspeptin/ GPR54 mRNA信号通路是否对雌激素(E)/孕激素(P)诱导的LH激增的产生至关重要。我们还将评估腹侧脑室周围核（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激增产生的影响的可能性。第二个目的是研究kisspeptin在青春期开始和性分化的黄体生成素激增机制中的作用。在这些实验中，我们将评估kisspeptin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。我们还将研究青春期是否与kisspeptin刺激GnRH神经元活性的能力增加有关。此外，我们将通过评估在GPR54 KOs的GnRH神经元中引入功能性GPR54基因的效果，来确定GnRH神经元中的kisspeptin/GPR54信号是否在青春期中起关键作用。最后，我们将研究KiSS-1和GPR54表达的性别差异是否归因于新生儿关键期的组织过程或青春期激素依赖的激活事件。阐明kisspeptin在女性促性腺激素分泌的发育和调节中的作用，可以提高我们对人类特发性促性腺激素功能低下的认识，并为改进治疗性早熟或性迟缓和不孕症的疗法提供科学依据。同样可以想象的是，这些知识可以作为开发新的更好的激素避孕策略的基础。

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.