Lesch-Nyhan Disease: A Model for Complex Genetic, Proteomic, and Metabolic Pathwa

描述（由申请人提供）： Lesch Nyhan病（LND）代表了一种理想的人类疾病模型，在该模型中研究甚至单个基因缺陷产生非常复杂的正常基因组、蛋白质组、生物化学和代谢组学变化功能的破坏的机制。LND是一种彻底表征但知之甚少的代谢和神经行为障碍，其特征在于代谢和神经功能障碍，由编码嘌呤再利用酶HPRT的基因突变引起。虽然对HPRT缺乏对嘌呤代谢的影响了解很多，但对复杂疾病表型的机制了解甚少。因此，我们建议将加州圣地亚哥大学和约翰霍普金斯大学的一些研究人员的兴趣和专业知识聚集在一起，通过哺乳动物和酵母模型系统中HPRT缺乏的transoriptional，蛋白质组学，生物化学发育，代谢组学影响，对这种疾病进行广泛的系统网络和途径。该项目的研究人员在HPRT缺乏问题和技术发展方面取得了重大进展，如人类蛋白质组表征，代谢组学研究的计算方法和利用yfeast模型系统表征人类疾病中的遗传畸变。我们将统一这些方法 整合到一个综合项目中，试图识别和理解嘌呤缺陷与复杂HPRT缺乏症表型的联系机制。

DESCRIPTION (provided by applicant): Lesch Nyhan Disease (LND) represents an ideal model human disease in which to study the mechanisms by which even single gene defects produce very complex disruptions of normal genomic, proteomic, biochemical and metabolomic changes function. LND is a thoroughly characterized but poorly understood metabolic and neurobehavioral disorder characterized by metabolic and neurological dysfunction and caused by mutations in the gene that encodes the purine reutilization enzyme HPRT. Although much is known about the effects of HPRT deficiency on purine metabolism, there is little understanding of the mechanisms responsible for the complex disease phenotype. We therefore propose to bring together the interests and expertise of a number of investigators at the University of California San Diego and Johns Hopkins University to undertake a broad systems networks and pathways approach to this disorder through the transoriptional, proteomic, biochemical developmental, metabolomic effects of HPRT deficiency in both the mammalian and the yeast model systems. The investigators included in this project have long individual histories of major advances to the problem of HPRT deficiency and to the development of technologies such as human proteome characterization, computational approaches to metabolomic studies and utilization of the yfeast model system for characterization of genetic aberrations in human disease. We shall unify these approaches into an integrated program in an attempt to identify and understand the mechanisms that tie the purine defect to the complex HPRT deficiency disease phenotype.