Integrative Analysis of Wilson's Disease

描述（由申请方提供）：本研究的长期目的是提供对威尔逊病（WD）的详细机制理解。WD是由铜转运蛋白ATP 7 B突变引起的一种严重且可能致命的人类铜稳态紊乱。该疾病与组织中的铜过载，特别是在肝脏中，以及广泛的肝脏、神经和精神异常有关。目前，铜触发WD的具体分子途径知之甚少。拟议的研究将使用基于现代方法的多学科方法来确定导致WD发作和进展的生化和细胞事件。测量谷胱甘肽和蛋白质氧化态的实验将确定WD中铜是否通过改变细胞室的氧化还原环境起作用（具体目标1）。hnRNP A2在细胞对铜过载的反应中的作用将通过表征其细胞内定位、相互作用蛋白和受hnRNPA 2上调影响的转录物子集来确定（特异性目的2）。Atp 7 b-/-小鼠脑中的代谢变化将通过将时间依赖性铜分布与疾病不同阶段的脂质和mRNA谱变化相关来表征（具体目标3）。将结合分子和代谢变化分析评价细胞损伤和行为变化。 公共卫生相关性：该项目的重点是阐明威尔逊病的病理发展机制，威尔逊病是一种严重的人类遗传性疾病，具有肝脏和神经系统表现。这些研究将确定威尔逊病病理变化发展和进展的关键分子因素和过程。这一结果将有助于提高诊断和治疗这种潜在的致命性铜代谢紊乱。

DESCRIPTION (provided by applicant): The long term of this study is to provide detailed mechanistic understanding of Wilson's disease (WD). WD is a severe and potentially fatal human disorder of copper homeostasis, caused by mutations in the copper transporter ATP7B. The disease is associated with copper overload in tissues, particularly in the liver, and a wide spectrum of hepatic, neurologic, and psychiatric abnormalities. Currently, specific molecular pathways through which copper triggers WD are poorly understood. The proposed studies will use a multidisciplinary approach based on modern methodologies to identify biochemical and cellular events that lead to the onset and progression of WD. The experiments measuring oxidation state of glutathione and proteins will determine whether in WD copper acts by modifying the redox environment of cellular compartments (Specific Aim 1). The role of hnRNP A2 in cell response to copper overload will be determined by characterizing its intracellular localization, interacting proteins, and a subset of transcripts affected by hnRNPA2 up-regulation (Specific Aim 2). Metabolic changes in the brain of Atp7b-/- mice will be characterized by corelating time-dependent copper distribution with changes in lipids and mRNA profiles at different stages of the disease (Specific Aim 3). Cell injury and behavior changes will be evaluated in conjunctions with analysis of molecular and metabolic changes. PUBLIC HEALTH RELEVANCE: The project focuses on elucidating the mechanisms of pathology development in Wilson's disease, a severe genetic disorder in humans with hepatic and neurologic manifestations. The studies will identify key molecular factors and proceses that underlie the development and progresion of pathologic changes in Wilson's disease. The results will contribute to improvement of diagnostic and treatment of this potentially fatal disorder of copper metabolism.