Integrative Analysis of Wilson's Disease

威尔逊病的综合分析

基本信息

批准号：
8387888
负责人：
SVETLANA LUTSENKO
金额：
$ 40.18万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8387888
关键词：
ATP phosphohydrolase Acute Liver Failure Affect Animal Model Animals Biochemical Brain Brain Mass Brain region Cell Nucleus Cell model Cells Copper Cytosol Development Diagnostic Disease Down-Regulation Early Diagnosis Electron Microscopy Environment Equilibrium Event Fatty Acids Fluorescence Gene Expression Profile Genes Genotype Glutathione Glutathione Disulfide Hepatic Hepatolenticular Degeneration Hereditary Disease Homeostasis Human Immunohistochemistry Impairment Label Lead Link Lipids Literature Liver Longitudinal Studies Maintenance Mass Spectrum Analysis Measures Mediating Messenger RNA Metabolic Metabolic Pathway Metabolism Methodology Modeling Molecular Molecular Analysis Mus Mutate Mutation Neurologic Neurologic Manifestations Neurologic Symptoms Neurons Nuclear Proteins Oxidation-Reduction Pathologic Pathology Pathway interactions Patients Pattern Phenotype Process Proteins RNA RNA Splicing RNA-Binding Proteins Roentgen Rays Role Severity of illness Spectrum Analysis Staging Symptoms Testing Time Tissues Transcript Up-Regulation Variant Wilson disease protein absorption base behavior change behavior test cell behavior cell growth cell injury glutathione peroxidase hnRNP A2 insight interdisciplinary approach lipid biosynthesis lipid metabolism liver transplantation metalloenzyme mind control myelination oxidation research study response sensor small hairpin RNA trafficking

项目摘要

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.

描述（由申请人提供）：本研究的长期目的是提供对威尔逊病（WD）的详细机制了解。 WD 是一种严重且可能致命的人类铜稳态紊乱，由铜转运蛋白 ATP7B 突变引起。该疾病与组织（特别是肝脏）铜超载以及广泛的肝脏、神经和精神异常有关。目前，人们对铜触发 WD 的具体分子途径知之甚少。拟议的研究将采用基于现代方法学的多学科方法来识别导致 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态的实验将确定 WD 中铜是否通过改变细胞区室的氧化还原环境发挥作用（具体目标 1）。 hnRNP A2 在细胞对铜超载反应中的作用将通过表征其细胞内定位、相互作用的蛋白质以及受 hnRNPA2 上调影响的转录子子集来确定（具体目标 2）。 Atp7b-/- 小鼠大脑代谢变化的特征是，将时间依赖性铜分布与疾病不同阶段的脂质和 mRNA 谱的变化相关联（具体目标 3）。细胞损伤和行为变化将结合分子和代谢变化的分析进行评估。公共健康相关性：该项目的重点是阐明威尔逊氏病的病理发展机制，威尔逊氏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生和进展的关键分子因素和过程。研究结果将有助于改善这种潜在致命的铜代谢紊乱的诊断和治疗。