The Genetic Basis of the Neuroendocrine Control of Reproduction

项目I：了解人类GnRH的发育生物学是复杂的，但对 深入了解几种人类生殖疾病一些关键基因/蛋白质已被确定， GnRH神经元迁移的发育途径，其中一些使用独特的人类模型， 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）。KAL 1是第一个 10年前通过非常仔细的临床和基因研究发现的。这种基因已经 GnRH神经元迁移的生理学相当轻。三个新基因已经被 在本中心赠款的最后一个周期中发现（本项目小组发现2个）-GPR 54及其配体KISS 1， FGFR1项目I现在将关注FGFR 1。 拥有世界上最大的IHH/KS人口，汇集了一批训练有素的人才， 获得定量表型分析和进行人类遗传研究，现在有实验室 由于我们有能力筛选这一领域的所有基因，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）在生殖系统中进行详细的基因型-表型相关性分析， 引起IHH的新基因FGFR 1;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 定义了每种基因型治疗的临床结果。最后，我们将研究生物影响， 突变受体的体外实验。 在我们上一个赠款周期中，这一调查路线已被证明是一个富有成果的研究领域， 希望继续阐明什么是越来越清楚的“GnRH神经元迁移途径”，所有在 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.