Neuroendocrine & Gonadal Control of Male Reproduction

神经内分泌

• 批准号: 7930121
• 负责人: William Francis Crowley
• 金额: $ 26.41万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7930121
• 关键词: Neuroendocrine; Gonadal; Control; Male; Reproduction

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.

描述(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翻译研究。它的多学科调查小组和人类基因分型和表型核心现在专注于利用其可用独特的人类种群控制生殖的神经内分泌的遗传学。在过去的一个周期中，该团队发现了三个新的基因，它们明显控制人类GnRH神经元的迁移和/或功能，并在突变时导致男性和女性的性腺功能减退。这些结果表明，这三个基因显然都是人类生殖能力的关键守门人。因此，项目I(Ki=W.Crowley)现在建议表征特发性低促性腺激素减退症(IHH)和Kallmann综合征(KS)FGFR1突变的全部表型/基因谱；将它们与KAL1突变进行比较；继续在这一不断演变的“GnRH神经元迁移途径”中寻找新的基因；并研究它们的体外生物学。项目II(Ki=S.Seminara)现在将扩大导致IHH的Gpr54和KiSS-1基因突变的表型；检查人类中KiSS-1基因产物Metastin的生理学；并检查Metastin对人类GnRH分泌的生物影响；并将小鼠中KISS speptin1基因敲除的表型与我们的Gpr54基因敲除的表型进行对比。最后，项目III(Ki=U·Kaiser)将研究GPR54‘S在下丘脑(使用Gt1-7细胞)的细胞作用的分子机制；确定其受性类固醇的调节；并在体外检测在项目Li中发现的突变的生物活性。总而言之，这种协同方法的集合应该能更快地将这些真理转移到人类身上，这是我们中心的中心目标之一。