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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 该提案的长期目标是描述蛋白质过剩心肌病（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 αB 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) 和 以 PSC 为例。 DRC 的特点是肌肉细胞中结蛋白异常聚集，这种聚集似乎在 DRC 发病机制中发挥着核心作用。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）引起的人类充血性心力衰竭（CHF）中也观察到类似的蛋白质聚集体。然而，异常蛋白质聚集如何影响肌细胞功能仍不清楚。目前的提案重点关注泛素蛋白酶体 系统（UPS）介导的蛋白质周转，这是一个对细胞功能几乎所有方面都至关重要的细胞过程。中心假设是 DRC 的异常蛋白聚集特征损害了 UPS 的蛋白水解功能，代表 PSC 中的节点致病过程。 将追求这些具体目标：(1) 测试 CryAB 是否在 UPS 功能中具有必然作用，并确定完整小鼠中异常蛋白聚集与 UPS 损伤之间的相关性（可能是因果关系）。潜在的假设是，CryAB 的异常蛋白聚集而不是功能丧失会损害晶体病心脏中的 UPS。 (2) 测试细胞培养中异常蛋白质聚集与 UPS 损伤之间的因果关系。这是为了检验以下假设：通过表达突变体 CryAB 形成蛋白质聚集体足以损害 UPS 功能。 (3) 利用蛋白质组学发现结晶病小鼠心脏中积累的泛素化蛋白的身份。基本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。