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。在GnRH神经元迁移的发育途径中已经发现了一些关键基因/蛋白，其中一些基因/蛋白使用了特发性促性腺功能低下（IHH）或Kallmann综合征（KS）的独特人类模型。KAL1是10年前通过非常仔细的临床和基因调查发现的。该基因在GnRH神经元迁移的生理学上有相当大的启示。在本中心资助的最后一个周期中，已经发现了三个新基因（2个由本项目团队发现）——GPR54及其配体KISS1和FGFR1。项目一现在将重点放在FGFR1上。拥有世界上最大的IHH/KS种群，聚集了一批训练有素的人才核心，以获得定量表型并进行人类遗传研究，现在拥有实验室能力筛选该领域的所有基因，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)对导致IHH的新基因FGFR1进行详细的基因型-表型相关性研究；3)对比FGFR1和KAL1突变的表型。这个

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.