The Genetic Basis of the Neuroendocrine Control of Reproduction in the Human

项目一：了解人类GnRH的发育生物学是复杂的，但对于深入了解几种人类生殖疾病至关重要。已经在GnRH神经元迁移的发育途径中鉴定了一些关键基因/蛋白质，其中一些使用了特发性低促性腺激素性腺功能减退症（IHH）或卡尔曼综合征（KS）的独特人类模型。KAL 1是10年前通过非常仔细的临床和遗传研究首次发现的。该基因为GnRH神经元迁移的生理学提供了相当多的线索。在该中心资助的最后一个周期中，现已发现了三个新基因（本项目团队发现了2个）-GPR 54及其配体，KISS 1和FGFR 1。项目I现在将关注FGFR 1。拥有世界上最大的IHH/KS人口，聚集了一批训练有素的人才核心，以获得定量表型分析和进行人类遗传研究，现在拥有筛选该领域所有基因的实验室能力，我们现在处于有利地位：1）使用遗传技术发现对生殖重要的新基因; 2）在引起IHH的新基因FGFR 1中进行详细的基因型-表型相关性;和3）对比FGFR 1和KAL 1突变的表型。的 这些资源的汇合将使我们能够开发KAL 1和FGFR 1的临床预测因子，并确定每种基因型治疗的临床结果。最后，我们将在体外研究突变受体的生物学影响。在我们上一个资助周期中，这一研究路线已被证明是一个富有成果的研究领域，并有望继续阐明越来越清楚的“GnRH神经元迁移途径”，所有这些都在研究中。 人类

Project I: Understanding the developmental biology of GnRH in the human is complex but critical to gaining insight into several human reproductive disorders. A few key genes/proteins have been identified in developmental pathways of GnRH neuronal migration, several of them using the unique human model of idiopathic hypogonadotropic hypogonadism (IHH) or Kallmann Syndrome (KS). KAL1 was the first to be discovered 10 years ago through very careful clinical and genetic investigations. This gene has shed considerable light on the physiology of GnRH neuronal migration. Three new genes have now been discovered (2 by this Project's team) during the last cycle of this Center grant - GPR54 and its ligand, KISS1, and FGFR1. Project I will now focus on FGFR1. Having the largest IHH/KS population in the world, assembled a talented Core of well-trained individuals to obtain quantitative phenotyping and perform human genetic studies, and now having the laboratory capabilities to screen all of the genes in this area, we are now well positioned: 1) to use genetic techniques to discover new genes important for reproduction; 2) to perform detailed genotype-phenotype correlations in a new gene FGFR1 causing IHH; and 3) to contrast the phentypes of FGFR1 and KAL1 mutations. The confluence of these resources will now allow us to develop clinical predictors for KAL1 and FGFR1 as well as define the clinical outcomes to treatment for each genotype. Finally, we will examine the biologic impact of the mutant receptors in vitro. This line of investigation has proven to be a fruitful area of research during our previous Grant cycle and will hopefully continue to elucidate what is increasingly clear as a 'GnRH neuronal migration pathway', all in the human.