Kisspeptin Physiology in the Human

描述(由申请人提供)：在生殖过程中，所有环境和内源性线索最终集中在单一的神经内分泌途径上，即来自下丘脑的促性腺激素释放激素(GnRH)及其对来自脑下垂体的黄体生成素(LH)和卵泡刺激素(FSH)的刺激。GnRH传统上被认为是生殖级联反应的第一步；它在这一生物学层次中的主导作用使其能够控制脉动性促性腺激素的分泌，调节性腺激素反馈，并最终决定青春期发育和生育的启动。2003年，我们报道，在人类和小鼠中，GPR54的突变导致了正常的脉动性GnRH释放模式的失败和性腺激素减退。GPR54的配体是Kisspeptin--Kisspeptin/GPR54对GnRH分泌的影响在哺乳动物中被很好地保守；它是一个遗传决定因素，是正常生殖功能的无可争议的守门人。Kispeptin是一种强大的促性腺激素释放激素分泌的刺激物，也是激活下丘脑垂体性腺轴的重要药物。这笔赠款现在将以人类为模型生物，探索Kispeptin途径的生理学。第一个特定的目的是使用精心组装的下丘脑标本来研究Kispeptin的蛋白表达，这些标本来自代表生殖生活的所有阶段，包括婴儿的微青春期、童年的平静、青春期过渡、生殖成熟和更年期。第二个特定目的是利用Kispeptin在体内询问GnRH神经元。对于表型和基因分型都很严格的性腺激素减退症患者使用Kisspeptin，可以评估GnRH神经元的功能完整性，包括GnRH神经元命运规范、多肽合成和释放的特性。第三个具体目的是使用多种给药方法来选择性地操纵生殖级联反应(选择性、可逆性抑制或持续刺激)，并探索其作为潜在治疗靶点的作用。与公共健康相关：我们的团队致力于发现控制人类青春期时间和生殖功能的基因。利用遗传工具，我们发现了一条配体-受体途径(Kispeptin-Gpr54)，似乎在这一过程中发挥了关键作用。Kispeptin通过GPR54发挥作用，刺激另一种下丘脑激素GnRH的释放，从而触发生殖荷尔蒙的级联反应。这笔赠款的主要重点是以人类为模式生物研究Kispeptin Gpr54途径的生理学，并探索Kispeptin可能成为生殖疾病患者的治疗靶点的可能性。这笔拨款的第一个目标将是研究从新生儿到更年期的整个生殖寿命内人类下丘脑中Kispeptin的表达。下一个目标将是给青春期发育异常的患者使用Kispeptin，以探索他们的GnRH神经元的功能。最终目标是通过不同的给药途径给药，并确定这种多肽是否可以作为生殖疾病患者的一种可能的治疗方法。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Our team is driven to discover the genes that control the timing of puberty and reproductive function in the human. Using genetic tools, we uncovered a ligand - receptor pathway (kisspeptin - GPR54) that appears to play this critical role in this process. Kisspeptin, acting through GPR54, stimulates the release of another hypothalamic hormone, GnRH, which triggers the reproductive hormonal cascade. The main focus of this grant is to study physiology of the kisspeptin GPR54 pathway using the human being as the model organism and to explore the possibility that kisspeptin could be a therapeutic target for patients with reproductive diseases. The first goal of this grant will be to study the expression of kisspeptin in human hypothalami from individuals across the reproductive lifespan, beginning with neonatal life all the way through to menopause. The next goal will be to administer kisspeptin to patients with abnormalities in pubertal development to probe the function of their GnRH neurons. The final goal will be to give kisspeptin via different routes of administration and determine whether this peptide could be a possible therapy in patients with reproductive disease.