Neuroendocrine & Gonadal Control of Male Reproduction

神经内分泌

• 批准号: 6909694
• 负责人: William Francis Crowley
• 金额: $ 128.16万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6909694
• 关键词: clinical research; cooperative study; gene mutation; gonadotropin releasing factor; neuroendocrine system; reproductive development

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（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。它的多学科研究小组和人类基因分型和表型核心现在专注于神经内分泌控制生殖的遗传学，使用独特的人类种群。在过去的周期中，该小组确定了三个新的基因，这些基因明显控制人类GnRH神经元的迁移和/或功能，并在突变时导致男性和女性的低促性腺激素性性腺功能减退症。这些结果表明，所有这三个显然是人类生殖能力的关键守门人。因此，项目I（KI = W。Crowley）现在提出了特发性低促性腺激素性性腺功能减退症（IHH）和卡尔曼综合征（KS）中FGFR 1突变的完整表型/基因型谱的特征;将其与KAL 1突变进行对比;继续在这种不断发展的“GnRH神经元迁移途径”中寻找新基因;并检查其体外生物学。项目二（KI = S. Seminara）现在将扩大导致IHH的GPR 54和KISS-1基因突变的表型;检查人类KiSS-1基因产物metastin的生理学;检查metastin给药对人类GnRH分泌的生物学效应;并将小鼠中kisspeptin 1敲除的表型与我们的GPR 54敲除的表型进行对比。最后，项目III（KI = U。Kaiser）将研究GPR 54在下丘脑中细胞作用的分子机制（使用GT 1 -7细胞）;定义性类固醇对其的调节;并在体外研究项目II中鉴定的突变的生物活性。总之，这种协同方法的集合应该提供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。