SD COBRE: UBIQUITIN-PROTEASOME IN CARDIAC REMODELING AND FAILURE

SD COBRE：泛素蛋白酶体在心脏重构和衰竭中的作用

• 批准号: 7720647
• 负责人: XUEJUN WANG
• 金额: $ 16.18万
• 依托单位: UNIVERSITY OF SOUTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720647
• 关键词: Affect; Cardiac; Cardiomyopathies; Cell Aggregation; Cell physiology; Characteristics; Computer Retrieval of Information on Scientific Projects Database; Congestive Heart Failure; Crystallins; Cultured Cells; Desmin; Failure; Funding; Genes; Goals; Grant; Heart; Heart Diseases; Human; Impairment; Institution; Link; Mediating; Mus; Muscle Cells; Mutation; Nodal; Pathogenesis; Play; Primary idiopathic dilated cardiomyopathy; Process; Proteins; Proteomics; Research; Research Personnel; Resources; Role; Source; Structural Protein; System; Testing; Ubiquitin; United States National Institutes of Health; genetic regulatory protein; loss of function; multicatalytic endopeptidase complex; mutant; protein aggregate; protein aggregation; protein degradation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A long term goal of this proposal is to delineate the mechanisms by which protein surplus cardiomyopathies (PSCs) progress to congestive heart failure. PSCs are an emerging group of cardiomyopathies. Crystallinopathy caused by the mutation of the alphaB-crystallin (CryAB) gene, often presents as desmin-related cardiomyopathy (DRC) and exemplifies PSCs. DRC is characterized by aberrant desmin aggregation in muscle cells and this aggregation appears to play a central role in DRC pathogenesis. Notably, similar protein aggregates were also observed in human congestive heart failure (CHF) resulting from idiopathic dilated cardiomyopathy, a common heart disease. However, it remains unclear how abnormal protein aggregation affects myocyte functions. The current proposal focuses on the ubiquitin-proteasome system (UPS) mediated protein turnover, a cellular process essential to virtually all aspects of cell function. The central hypothesis is that aberrant protein aggregation characteristic of DRC impairs proteolytic function of the UPS, representing a nodal pathogenic process in PSCs. These specific aims will be pursued: (1) To test whether CryAB has an obligatory role in UPS function and to define a correlation (likely a causal relation) between aberrant protein aggregation arid UPS impairment in intact mice. The underlying hypothesis is that aberrant protein aggregation instead of loss-of-function of CryAB impairs the UPS in crystallinopathic hearts. (2) To test a cause-effect link between aberrant protein aggregation and UPS impairment in cell culture. This is to test the hypothesis that formation of protein aggregates through expression of a mutant CryAB is sufficient to compromise UPS function. (3) To discover the identities of ubiquitylated proteins accumulated in crystallinopathy mouse hearts using proteomics. Underlying hypothesis is that accumulated ubiquitylated proteins include structural proteins and physiologically important regulatory proteins.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 这项建议的长期目标是阐明蛋白过剩心肌病（PSC）进展为充血性心力衰竭的机制。PSC是一组新兴的心肌病。由α B-晶体蛋白（CryAB）基因突变引起的晶体病通常表现为结蛋白相关性心肌病（DRC）， 确认PSC。DRC的特征在于肌细胞中异常结蛋白聚集，并且这种聚集似乎在DRC发病机制中起核心作用。值得注意的是，在由特发性扩张型心肌病（一种常见的心脏病）引起的人充血性心力衰竭（CHF）中也观察到类似的蛋白质聚集体。然而，目前尚不清楚异常蛋白质聚集如何影响肌细胞功能。目前的建议集中在泛素-蛋白酶体 UPS系统（UPS）介导的蛋白质周转，这是一个对细胞功能的几乎所有方面都至关重要的细胞过程。中心假设是，异常的蛋白质聚集特性的DRC损害蛋白水解功能的UPS，代表一个节点的PSC的致病过程。 这些具体目标将被追求：（1）测试CryAB是否在UPS功能中具有强制性作用，并定义正常小鼠中异常蛋白质聚集和UPS损伤之间的相关性（可能是因果关系）。潜在的假设是，异常蛋白质聚集而不是CryAB的功能丧失损害了堆叠性心脏中的UPS。(2)检测细胞培养中异常蛋白质聚集和UPS损伤之间的因果关系。这是为了检验通过表达突变体CryAB形成蛋白质聚集体足以损害UPS功能的假设。(3)应用蛋白质组学方法研究堆叠病小鼠心脏中泛素化蛋白的特性。潜在的假设是，积累的泛素化蛋白包括结构蛋白和生理上重要的调节蛋白。