Control of Reproduction by an Inhibitory RFamide Peptide

描述（由申请人提供）：无数激素分泌的定时和协调是维持体内平衡和最佳身体功能所必需的。传统上，内分泌学家将负反馈机制和神经内分泌脉冲发生器作为调节激素分泌时间模式的主要机制。然而，越来越清楚的是，内源性定时系统在这种调节中起着至关重要的作用。我们最近发现含有一种新型抑制肽，促性腺激素抑制激素（GnlH）的细胞在叙利亚仓鼠和其他啮齿动物的大脑中高度定位，纤维从中隔扩散到尾侧下丘脑。重要的是，我们的试点工作表明，大脑或外周注射GnlH以剂量依赖的方式抑制LH。此外，GnlH系统投射到促性腺激素释放激素（GnRH）神经元，允许直接，抑制GnRH分泌的控制。起源于位于视交叉上核（SCN）的大脑时钟的纤维与GnlH细胞体形成紧密的对应，提供了一种潜在的时间控制手段。最后，GnlH细胞含有雌激素受体，对雌二醇刺激有反应，提示雌激素作用于这些细胞调节类固醇负反馈。总之，这些发现表明GnlH系统被组织来调节生殖功能和下丘脑-垂体-性腺（HPG）轴。本研究旨在进一步探索GnlH系统与HPG轴生殖控制机制相结合的神经解剖学和功能手段。该建议将建立1)从内源性生物钟到GnlH系统的精确通信手段，2)从GnlH系统到生殖轴，以及3)这个新系统与生殖轴之间相互作用的功能后果。激素分泌时间的中断对人体健康有明显的不利影响。例如，时差和倒班工作导致各种生殖障碍，并增加患内分泌反应性肿瘤的风险。该建议旨在了解负责激素定时的神经机制，以帮助指导这些内分泌疾病的治疗/预防。

DESCRIPTION (provided by applicant): The timing and coordination of the secretion of myriad hormones is necessary for the maintenance of homeostasis and optimal body functioning. Traditionally, endocrinologists have focused on the role of negative feedback mechanisms and neuroendocrine pulse generators as the primary mechanisms regulating the temporal pattern of hormone secretion. However, it is becoming increasingly clear that endogenous timing systems play a crucial role in this regulation. We recently found that cells containing a novel inhibitory peptide, gonadotropin-inhibitory hormone (GnlH), are highly localized in the brains of Syrian hamsters and other rodents, with fibers projecting diffusely from the septum to the caudal hypothalamus. Importantly, our pilot work shows that brain or peripheral injections of GnlH inhibit LH in a dose-dependent manner. Furthermore, the GnlH system projects to gonadotropin-releasing-hormone (GnRH) neurons, permitting direct, inhibitory control of GnRH secretion. Fibers originating in the brain clock located in the suprachiasmatic nucleus (SCN) form close appositions with GnlH cell bodies, providing a potential means of temporal control. Finally, GnlH cells contain estrogen receptors and respond to estradiol stimulation, suggesting that estrogen acts on these cells to regulate steroid negative feedback. Together, these findings indicate that the GnlH system is organized to modulate reproductive function and the hypothalamo-pituitary- gonadal (HPG) axis. The present proposal is designed to further explore the neuroanatomical and functional means by which the GnlH system is integrated with well understood mechanisms of reproductive control of the HPG axis. This proposal will establish the precise means of communication 1) from the endogenous circadian clock to the GnlH system, 2) from the GnlH system to the reproductive axis, and 3) the functional consequences of the interactions between this novel system and the reproductive axis. Disruptions in the timing of hormone secretion have pronounced adverse effects on human health. For example, jet lag and shift work lead to a variety of reproductive disturbances and an increased risk of developing endocrine-responsive tumors. This proposal seeks to understand the neural mechanisms responsible for hormonal timing to help guide the treatment/prevention of these endocrine disorders.