Neuroendocrine & Gonadal Control of Male Reproduction

简介（由申请人提供）：在过去的15年里，哈佛生殖内分泌科学中心一直致力于人类生殖的转化研究。其多学科调查小组和人类基因分型和表型分型核心现在专注于利用独特的人类种群进行生殖神经内分泌控制的遗传学。在过去的周期中，该团队发现了三个新的基因，它们清楚地控制人类GnRH神经元的迁移和/或功能，并在男性和女性发生突变时导致促性腺功能低下。这些结果表明，这三者显然是人类生殖能力的关键看门人。

DESCRIPTION (provided by applicant): During the past 15 years, The Harvard Reproductive Endocrine Sciences Center has been dedicated to translational research in reproduction in the human. Its multidisciplinary investigative team and Human Genotyping and Phenotyping Core has now focused on the genetics of the neuroendocrine control of reproduction using unique human populations available to it. During the past cycle, this team identified three new genes that clearly control the migration and/or functioning of GnRH neurons in the human and cause hypogonadotropic hypogonadism in both men and women when mutated. These results indicate that all three are clearly key gatekeepers of reproductive competency in the human. Hence, Project I (KI = W. Crowley) now proposes to characterize the full phenotype/genotype spectrum of FGFR1 mutations in Idiopathic Hypogonadotropic Hypogonadisms (IHH) and Kallmann Syndrome (KS); contrast them with mutations in KAL1; continue to search for new genes in this evolving "GnRH neuronal migratory pathway"; and examine their in vitro biology. Project II (KI = S. Seminara) will now expand the phenotype of mutations in the GPR54 and KISS-1 genes causing IHH; examine the physiology of metastin, the gene product of KiSS-1, in the human; and examine the biologic effects of metastin administration on GnRH secretion in humans; and contrast the phenotype of the kisspeptin1 knock-out in the mouse with that of our GPR54 knockout. Finally, Project III (KI = U. Kaiser) will examine the molecular mechanisms of GPR54's cellular action in the hypothalamus (using GT1-7 cells); define its regulation by sex steroids; and examine the biologic activity of mutations identified in Project lI, in vitro. Together, this ensemble of synergistic approaches should provide swifter transfer of these truths into the human, one of the central goals of our Center.