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.

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