Kisspeptin/GPR54 in the Female Neuroendocrine Axis

描述（由申请人提供）：KiSS-1 基因编码称为 Kisspeptins 的肽家族，该肽家族与称为 GPR54 的 G 蛋白偶联受体结合。 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性性腺功能减退症。 Kisspeptins 刺激促性腺激素释放激素 (GnRH) 和促性腺激素（LH 和 FSH）的分泌，并且 KiSS-1 基因受性腺类固醇调节——这表明 Kisspeptin 通过 GPR54 的信号传导在生殖的神经内分泌调节中发挥作用。本研究的总体目标是了解 Kisspeptins 在调节雌性大鼠和小鼠促性腺激素分泌中的生理功能。我们的首要目标是评估 Kisspeptins 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 信号通路对于雌激素 (E)/黄体酮 (P) 诱导的 LH 激增的产生是否至关重要。我们还将评估前腹侧室周核 (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 浪涌产生的影响的可能性。第二个目标是研究 Kisspeptins 在青春期开始和 LH 激增机制的性别分化中的作用。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 Kisspeptins 刺激 GnRH 神经元活性的能力增强有关。此外，我们将通过评估将功能性 GPR54 基因引入 GPR54 KO 的 GnRH 神经元中的效果，确定 GnRH 神经元中的 Kisspeptin/GPR54 信号传导是否在青春期中发挥关键作用。最后，我们将研究 KiSS-1 和 GPR54 表达的性别差异是否可归因于新生儿关键期的组织过程或青春期激素依赖性激活事件。阐明 Kisspeptins 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低促性腺激素性腺功能减退症的理解，并可能为改进治疗早熟或青春期延迟和不孕症的疗法提供科学依据。还可以想象，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.