Kisspeptin Physiology in the Human

在繁殖过程中，所有环境和内源线索最终都会汇聚到 促性腺激素释放激素(GnRH)单一共同神经内分泌途径 来自下丘脑及其对黄体生成素和卵泡的刺激 来自脑下垂体的刺激素(FSH)。GnRH传统上被认为是 生殖级联的第一步；它在生物等级中的主导作用 允许它控制搏动性促性腺激素的分泌，调节性腺类固醇的反馈， 并最终决定青春期发育和生育的启动。2003年，我们 报道称，在人类和小鼠中，Gpr54基因的突变导致了 搏动性GnRH释放和低促性腺激素减退的正常模式。 GPR54的配体是Kisspeptin--Kisspeptin/GPR54对GnRH分泌的影响 在哺乳动物物种中非常保守；它是一种遗传决定因素， 无可争议的正常生殖功能的守门人。 Kispeptin是一种强大的促性腺激素释放激素分泌的刺激物，是激活 下丘脑-垂体-性腺轴。。这项资助现在将探索生理学 以人为模型生物体的Kispeptin途径。第一个具体 目的利用精心组装的方法研究Kispeptin的蛋白表达 下丘脑样本来自代表生殖生活各个阶段的个体， 包括婴儿期的小青春期，童年的静止期，青春期的过渡期， 生殖成熟和更年期。第二个具体目标是利用Kispeptin 体内GnRH神经元的讯问。给予Kispeptin的治疗非常细致 表型和基因分型的性腺激素减退症患者将允许 对促性腺激素释放激素神经元功能完整性的评估，包括 促性腺激素释放激素神经元命运指定、多肽合成和释放。第三个具体目标 使用多种Kispeptin给药方法来选择性地操纵 生殖级联(选择性、可逆抑制或持续刺激)和 探索其作为潜在治疗靶点的作用。

In reproduction, all environmental and endogenous cues ultimately converge upon the single common neuroendocrine pathway of gonadotropin-releasing hormone (GnRH) from the hypothalamus and its stimulation of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the pituitary. GnRH has traditionally been thought of as the first step in the reproductive cascade; its commanding role in this biological hierarchy allows it to control pulsatile gonadotropin secretion, modulate gonadal steroid feedback, and ultimately determine the initiation of pubertal development and fertility. In 2003, we reported that, in both the human and the mouse, mutations in GPR54 cause a failure of the normal patterns of pulsatile GnRH release and hypogonadotropic hypogonadism. The ligand of GPR54 is kisspeptin--the impact of kisspeptin/GPR54 on GnRH secretion is well conserved across mammalian species; it is a genetic determinant and indisputable gatekeeper of normal reproductive function. Kisspeptin is a powerful stimulus of GnRH secretion and is a vital agent for activating the hypothalamic pituitary gonadal axis. . This grant will now explore the physiology of the kisspeptin pathway using the human as the model organism. The first specific aim explores the protein expression of kisspeptin using carefully assembled hypothalamic specimens from individuals representing all phases of reproductive life, including the mini-puberty of infancy, the childhood quiescence, the pubertal transition, reproductive maturity, and menopause. The second specific aim utilizes kisspeptin to interrogate of the GnRH neuron in vivo. Administration of kisspeptin to meticulously phenotyped and genotyped patients with hypogonadotropic hypogonadism will allow assessments of the functional integrity of the GnRH neuron, including the properties of GnRH neuronal fate specification, peptide synthesis and release. The third specific aim employs diverse methods of kisspeptin administration to selectively manipulate the reproductive cascade (selective, reversible suppression or sustained stimulation) and explore its role as a potential therapeutic target.