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汇聚于单一的共同神经内分泌途径，即来自下丘脑的促性腺激素释放激素（GnRH）及其刺激来自垂体的促黄体激素（LH）和促卵泡激素（FSH）。GnRH传统上被认为是生殖级联的第一步;它在这个生物层次中的指挥作用使其能够控制脉冲式促性腺激素分泌，调节性腺类固醇反馈，并最终决定青春期发育和生育力的开始。在2003年，我们报道，在人类和小鼠中，GPR 54突变导致脉冲式GnRH释放和低促性腺激素性性腺功能减退症的正常模式失败。GPR 54的配体是kisspeptin-kisspeptin/GPR 54对GnRH分泌的影响在哺乳动物物种中是保守的;它是一个遗传决定因素和正常生殖功能无可争议的守门人。Kisspeptin是GnRH分泌的强有力刺激物，并且是激活下丘脑垂体性腺轴的重要试剂。该基金将以人类为模型生物，探索kisspeptin通路的生理学。第一个具体的目标探讨kisspeptin的蛋白质表达，使用精心组装的下丘脑标本，从个人代表生殖生活的各个阶段，包括婴儿期的青春期，儿童期的静止，青春期的过渡，生殖成熟，和更年期。第二个具体目标是利用kisspeptin在体内询问GnRH神经元。将kisspeptin用于精确分型和基因分型的低促性腺激素性性腺功能减退症患者将允许评估GnRH神经元的功能完整性，包括GnRH神经元命运规范、肽合成和释放的特性。第三个具体目标采用kisspeptin给药的不同方法来选择性地操纵生殖级联反应（选择性、可逆抑制或持续刺激），并探索其作为潜在治疗靶点的作用。公共卫生相关性：我们的团队致力于发现控制人类青春期和生殖功能的基因。使用遗传工具，我们发现了一个配体-受体途径（kisspeptin -GPR 54），似乎在这一过程中发挥了关键作用。Kisspeptin通过GPR 54起作用，刺激另一种下丘脑激素GnRH的释放，从而引发生殖激素级联反应。该基金的主要重点是以人类为模式生物，研究kisspeptin GPR 54通路的生理学，并探索kisspeptin作为生殖疾病患者治疗靶点的可能性。这项资助的第一个目标将是研究kisspeptin在人类下丘脑中的表达，从新生儿开始，一直到更年期。下一个目标是将kisspeptin用于青春期发育异常的患者，以探测他们的GnRH神经元的功能。最终的目标将是通过不同的给药途径给予kisspeptin，并确定这种肽是否可能成为生殖疾病患者的一种治疗方法。

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.