Control of Reproduction by Two, Complementary RFamide Peptides

描述(申请人提供)：女性的生殖功能需要由位于视交叉上核(SCN)的昼夜节律主脑时钟对许多神经内分泌事件进行精确的时间组织。在包括人类在内的不同物种中，昼夜节律的扰乱会导致排卵和繁殖力的明显不足。我们的调查重点是 关于两个相互对立的关键神经肽的昼夜节律控制，促性腺激素抑制激素(GnIH，又称RFRP-3)和Kispeptin。在哺乳动物中，GnIH显著抑制促性腺激素释放激素(GnRH)的分泌和垂体促性腺激素的分泌，而Kispeptin是GnRH神经元网络的明显刺激因子。尽管GnIH和Kispeptin在哺乳动物生殖中的作用已经得到证实，而且人们知道昼夜节律系统是女性生殖轴的关键调节因素，但这些相互作用背后的特定神经化学途径还没有被很好地了解。本方案探讨了一系列昼夜节律振荡器如何与GnIH和Kispeptin信号通路相互作用来调节GnRH的分泌和排卵前GnRH/黄体生成素(LH)的激增。到目前为止，我们的工作表明，SCN单通道地投射到GnIH和Kispeptin系统，以适当地协调它们的激活状态，以允许GnRH/LH峰的启动和排卵。此外，我们最近在体外和体内的研究结果表明，在GnRH细胞中工作的自主生物钟在调节HPG轴对上游神经化学信号(包括Kispeptin)的日常反应中扮演了一个新的角色。本方案结合系统、回路、分子/遗传学和药理学的方法来研究GnIH、Kisspeptin和昼夜节律系统之间的相互作用，通过探索1)Kisspeptin和GnIH相互作用调节GnRH分泌的特定神经位点，2)SCN协调Kisspeptin和GnIH定时分泌的神经化学手段，以及3)这些相互作用对GnRH/Lh峰和排卵的功能影响。这项拟议的工作解决了调控生物学中的一个经典问题，并可能在开发安全/有效的避孕措施以及治疗人类的一系列生殖疾病方面产生实质性的翻译影响，包括性早熟和青春期延迟、不孕和多囊卵巢综合征。

DESCRIPTION (provided by applicant): Female reproductive functioning requires the precise temporal organization of numerous neuroendocrine events by a master circadian brain clock located in the suprachiasmatic nucleus (SCN). Across species, including humans, disruptions to circadian timing result in pronounced deficits in ovulation and fecundity. Our investigations focus on the circadian control of two key neuropeptides with opposing roles, gonadotropin-inhibitory hormone (GnIH, also known as RFRP-3) and kisspeptin. Across mammalian species, GnIH markedly inhibits the secretion of gonadotropin-releasing hormone (GnRH) and pituitary gonadotropin secretion, whereas kisspeptin is a pronounced stimulator of the GnRH neuronal network. Despite the well- established roles for both GnIH and kisspeptin in mammalian reproduction, as well as the knowledge that the circadian timing system is a crucial regulator of the female reproductive axis, the specific neurochemical pathways underlying these interactions are not well understood. The present proposal explores how a hierarchy of circadian oscillators interacts with the GnIH and kisspeptin signaling pathways to regulate GnRH secretion and the preovulatory GnRH/luteinizing hormone (LH) surge. Our work to date indicates that the SCN projects monosynaptically to the GnIH and kisspeptin systems to coordinate their activational states appropriately to allow for initiation of the GnRH/LH surge and ovulation. Additionally, our recent in vitro and in vivo findings point to a novel role for autonomous circadian clocks, operating in GnRH cells, in mediating daily responsiveness of the HPG axis to upstream neurochemical signaling, including kisspeptin. The present proposal combines system, circuit, molecular/genetic, and pharmacological approaches to investigate the interactions among the GnIH, kisspeptin, and circadian systems by exploring: 1) the specific neural loci at which kisspeptin and GnIH interact to regulate GnRH secretion, 2) the neurochemical means by which the SCN coordinates the timed secretion of kisspeptin and GnIH, and 3) the functional implications of these interactions for the GnRH/LH surge and ovulation. The proposed work addresses a classic question in regulatory biology, and has the potential for substantial translational impact in the development of safe/effective contraception, as well as the treatment of a host of reproductive disorders in humans, including precocious and delayed puberty, infertility, and polycystic ovarian syndrome.