Elucidating the Physiogical Role of GPR54 and its Ligan

项目II：在所有哺乳动物中，促性腺激素释放激素(GnRH)位于生殖级联的顶部，刺激脑下垂体分泌促性腺激素(LH)和卵泡刺激素(FSH)，然后刺激性腺。长期以来，对生殖生物学家和临床研究人员来说，理解GnRH分泌的控制机制(以复杂的脉动性和可变频率为特征)一直是一个挑战。利用GnRH分泌缺陷或缺失的特发性低促性腺激素减退症(IHH)的人类疾病模型，K1发现了一个基因Gpr54，它似乎是GnRH刺激生殖级联反应的守门人。由于人类的GPR54和小鼠的GPR54的突变都会导致性幼稚和性腺激素减退， GPR54的作用显然在多种哺乳动物物种中是保守的，是生殖能力和生育能力的主要决定因素。由于这是生殖生物学新一章的第一页，这项拨款结合了几种方法来揭示Gpr54及其配体Metastin的生理作用，Metastin是从一种名为Kisspeptin-1的蛋白质的蛋白质分解过程中衍生出来的。这些方法包括1)在更广泛的促性腺激素释放激素分泌异常患者群体中进行进一步的突变分析和遗传研究，2)开发和验证Metastin的分析方法，以绘制其在人类正常和病理生理状态下的生理学图，3)给男性和女性使用Metastin，以及4)基因敲除小鼠模型。这些信息将对理解和潜在地治疗许多影响生育的人类疾病至关重要。

Project II: In all mammals, gonadotropin releasing hormone (GnRH) sits atop the reproductive cascade, stimulating the secretion of tuteinizing hormone (LH) and follicle stimulating hormone (FSH) from the pituitary, which then stimulate the gonads. Understanding the control mechanisms for GnRH secretion (characterized by complex pulsatility and variable frequency) has long been a challenge for reproductive biologists and clinical investigators alike. Using the human disease model of idiopathic hypogonadotropic hypogonadism (IHH) in which GnRH secretion is defective or absent, the Kl has identified a gene, GPR54, that appears to act as a gatekeeper for GnRH stimulation of the reproductive cascade. Since mutations in both GPR54 in human and Gpr54 in mice cause sexual infantilism and hypogonadotropic hypogonadism, the effect of GPR54 is clearly conserved across multiple mammalian species and is a major determinant of reproductive competency and fertility. As this is the first page in a new chapter of reproductive biology, this grant incorporates several approaches to uncover the physiologic roles of GPR54 and its ligand, metastin, which is derived from proteolytic processing of a protein called kisspeptin-1. These approaches include 1) further mutation analysis and genetic studies in a broader population of patients with abnormalities in GnRH secretion, 2) development and validation of assays for metastin to chart its physiology in the human in normal and pathophysiologic states, 3) administration of metastin to men and women, and 4) knockout mouse models. This information will be critical to understand and potentially treat numerous human diseases that affect fertility.