Control of Reproduction by Two, Complementary RFamide Peptides

描述（由申请人提供）：女性生殖功能需要通过位于视交叉上核（SCN）的主昼夜节律脑钟对许多神经内分泌事件进行精确的时间组织。在包括人类在内的所有物种中，昼夜节律的中断会导致排卵和生殖力的明显不足。我们的调查重点是 对具有相反作用的两种关键神经肽的昼夜节律控制，促性腺激素抑制激素（GnIH，也称为RFRP-3）和kisspeptin。在哺乳动物中，GnIH显著抑制促性腺激素释放激素（GnRH）和垂体促性腺激素的分泌，而kisspeptin是GnRH神经元网络的显著刺激物。尽管GnIH和kisspeptin在哺乳动物生殖中的作用已得到充分确认，并且知道昼夜节律计时系统是雌性生殖轴的关键调节器，但这些相互作用背后的特定神经化学途径尚未得到充分理解。本提案探讨了昼夜节律振荡器的层次结构如何与GnRH和kisspeptin信号通路相互作用，以调节GnRH分泌和排卵前GnRH/促黄体生成素（LH）激增。我们迄今的工作表明，SCN项目单突触的GnIH和kisspeptin系统，以协调其激活状态，适当地允许启动GnRH/LH浪涌和排卵。此外，我们最近在体外和体内的研究结果指出，自主生物钟，在GnRH细胞中运作，在介导的HPG轴的上游神经化学信号，包括kisspeptin的日常反应的一种新的作用。本提案结合了系统，电路，分子/遗传和药理学方法，通过探索以下内容来研究GnIH，kisspeptin和昼夜节律系统之间的相互作用：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，和3）这些相互作用对GnRH/LH峰和排卵的功能影响。拟议的工作解决了调控生物学中的一个经典问题，并有可能在开发安全/有效的避孕方法以及治疗人类生殖疾病（包括性早熟和青春期延迟，不孕症和多囊卵巢综合征）方面产生实质性的翻译影响。

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.