Elucidating the Physiogical Role of GPR54 and its Ligan

项目二：在所有哺乳动物中，促性腺激素释放激素（GnRH）位于生殖级联的顶端，刺激垂体分泌促黄体激素（LH）和促卵泡激素（FSH），然后刺激性腺。了解GnRH分泌的控制机制（以复杂的脉动和可变频率为特征）长期以来一直是生殖生物学家和临床研究人员面临的挑战。使用特发性低促性腺激素性性腺功能减退症（IHH）的人类疾病模型，其中GnRH分泌缺陷或缺失，KI已经鉴定了似乎充当生殖级联的GnRH刺激的看门人的基因GPR 54。由于人的GPR 54和小鼠的GPR 54两者的突变都引起性功能障碍和低促性腺激素性性腺功能减退症， GPR 54的作用在多种哺乳动物物种中明显保守，并且是生殖能力和生育力的主要决定因素。由于这是生殖生物学新篇章的第一页，该资助纳入了几种方法来揭示GPR 54及其配体metastin的生理作用，metastin来源于一种名为kisspeptin-1的蛋白质的蛋白水解加工。这些方法包括：1）在GnRH分泌异常的更广泛患者人群中进行进一步的突变分析和遗传研究，2）开发和验证metastin测定法，以绘制其在正常和病理生理状态下的人体生理学，3）向男性和女性施用metastin，以及4）敲除小鼠模型。这些信息对于理解和治疗影响生育能力的许多人类疾病至关重要。

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.