Integrative Analysis of Wilson's Disease

描述（由申请人提供）：本研究的长期目的是详细了解威尔逊氏病（WD）的机制。WD是一种严重且可能致命的人类铜稳态紊乱，由铜转运体ATP7B突变引起。该疾病与组织中铜超载有关，特别是在肝脏中，以及广泛的肝脏、神经和精神异常。目前，铜触发WD的具体分子途径尚不清楚。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发病和进展的生化和细胞事件。测量谷胱甘肽和蛋白质氧化状态的实验将确定在WD中铜是否通过改变细胞区室的氧化还原环境起作用（Specific Aim 1）。hnRNPA2在细胞对铜超载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hnRNPA2上调影响的转录子子集来确定（Specific Aim 2）。Atp7b-/-小鼠大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（Specific Aim 3）。细胞损伤和行为改变将结合分子和代谢变化的分析来评估。

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.