Lesch-Nyhan Disease: A Model for Complex Genetic, Proteomic & Metabolic Pathways

Lesch Nyhan病（LND）是一种理想的人类疾病模型，其中通过以下方法来研究其机制： 即使是单个基因缺陷也会对正常的基因组，蛋白质组， 生物化学和代谢组学改变功能。LND是一种彻底表征但知之甚少的 以代谢和神经功能障碍为特征的代谢和神经行为障碍 by mutations突变in the gene基因that encoded编码the purine嘌呤reutilization再利用enzyme酶HPRT.尽管我们对 HPRT缺乏对嘌呤代谢的影响，其机制尚不清楚， 负责复杂的疾病表型。因此，我们建议将利益和 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专业知识 采取广泛的系统网络和途径，通过transoriptional， 蛋白质组学、生化发育、代谢组学的影响，HPRT缺乏症在哺乳动物和 酵母模型系统。该项目中的研究人员有很长的个人历史， HPRT缺陷问题的进展和技术的发展，如人类 蛋白质组特征，代谢组学研究的计算方法和YFEST的利用 用于表征人类疾病遗传变异的模型系统。我们将统一这些方法 一个综合的计划，试图确定和理解嘌呤缺陷的机制， 复杂的HPRT缺乏症表型。 相关性（参见说明）： 大多数人类遗传和代谢疾病的结果从非常复杂的相互作用的水平上的缺陷 基因、异常蛋白质和改变的代谢过程。我们建议研究这些方法， 复杂的相互作用因素导致儿童神经系统疾病莱施尼汉病。

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 andcaused by mutations in the gene that encodesthe 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 proposeto 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 nto a integrated program in an attempt to identify and understand the mechanisms that tie the purine defect to the complex HPRT deficiency disease phenotype. RELEVANCE (See instructions): Most human genetic and metabolic disease results from very complex interactions at the level of defective genes, abnormal proteins and altered metabolic processes. We propose to study that ways in which these omplex interacting factors cause the childhood neurological disorder Lesch Nyhan Disease.