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

描述(由申请人提供)： Lesch Nyhan病(LND)是一种理想的人类疾病模型，可以用来研究单基因缺陷导致正常基因组、蛋白质组、生化和代谢改变功能的非常复杂的破坏的机制。LND是一种特征全面但知之甚少的代谢和神经行为障碍，以代谢和神经功能障碍为特征，由编码嘌呤再利用酶HPRT的基因突变引起。虽然人们对HPRT缺乏对嘌呤代谢的影响了解很多，但对导致这种复杂疾病表型的机制却知之甚少。因此，我们建议汇集加州大学圣地亚哥分校和约翰·霍普金斯大学的一些研究人员的兴趣和专业知识，通过哺乳动物和酵母模型系统中HPRT缺乏的跨向、蛋白质组、生化、发育和代谢组学影响，对这种疾病进行广泛的系统网络和途径研究。该项目中包括的研究人员在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以及利用yfeast模型系统来表征人类疾病中的遗传异常。我们将统一这些方法 纳入一个综合计划，试图识别和了解将嘌呤缺陷与复杂的HPRT缺乏症表型联系起来的机制。

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.