The Genetic Basis of the Neuroendocrine Control of Reproduction

生殖神经内分泌控制的遗传基础

• 批准号: 7950548
• 负责人: William Francis Crowley
• 金额: $ 48.58万
• 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: 2009-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950548
• 关键词: Anosmia; Area; Clinical; Complex; Counseling; Defect; Development; Developmental Biology; Disease; Dominant-Negative Mutation; Exhibits; FGFR1 gene; Family; Future; Gene Proteins; Genes; Genetic; Genetic Techniques; Genetic screening method; Genotype; Goals; Gonadal structure; Grant; Human; Human Genetics; Hypothalamic structure; In Vitro; Individual; Investigation; KISS1 gene; KISS1R gene; Kallmann Syndrome; Laboratories; Ligands; Light; Modeling; Mutation; Neurons; Neurosecretory Systems; Outcome; Pathway interactions; Patients; Phenotype; Physiology; Population; Positioning Attribute; RNA Splicing; Reproduction; Research; Resources; Role; Signal Pathway; Therapeutic; Training; Upper arm; Variant; base; clinical phenotype; gene discovery; insight; male; migration; mutant; receptor; reproductive; response

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.

项目I：了解人类促性腺激素释放激素的发育生物学是复杂的，但对 洞察人类的几种生殖障碍。一些关键的基因/蛋白质已经在 促性腺激素释放激素神经元迁移的发育途径，其中几条途径使用了独特的人类模型 特发性促性腺激素减退症(IHH)或Kallmann综合征(KS)。KAL1是第一个 10年前通过非常仔细的临床和基因研究发现的。这个基因已经脱落了 对促性腺激素释放激素神经元迁移的生理学有相当大的了解。现在已经有三个新的基因 在本中心GRANT-GPR54及其配体KISS1的最后一个周期中发现(2个由本项目团队发现)， 和FGFR1。项目I现在将重点介绍FGFR1。 拥有世界上最大的IHH/KS人口，聚集了一支训练有素的人才核心，以 获得定量表型并进行人类遗传学研究，现在已经有了实验室 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)使用基因技术 发现对繁殖重要的新基因；2)进行详细的基因-表型相关性 导致IHH的新基因FGFR1；以及3)对比FGFR1和KAL1突变的表型。这个 这些资源的融合现在将使我们能够开发KAL1和FGFR1的临床预测因子 AS定义了每种基因型的临床治疗结果。最后，我们将检查生物影响 突变受体的体外实验。 在我们之前的赠款周期中，这一调查已被证明是一个富有成效的研究领域，并将 希望继续阐明什么是越来越清楚的GnRH神经元迁移途径，所有这些都在 人类。