Cytoskeletal-Associated Proteins and Cardiomyopathy

细胞骨架相关蛋白和心肌病

• 批准号: 7114922
• 负责人: KENNETH R CHIEN
• 金额: $ 36.35万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7114922
• 关键词: bioinformatics; biological signal transduction; biomechanics; cardiac myocytes; cytoskeletal proteins; electrocardiography; genetically modified animals; heart failure; hypertrophic myocardiopathy; laboratory mouse; mechanical stress; muscle proteins; myocardium disorder

DESCRIPTION (provided by applicant): Chronic increases in wall stress play a pivotal role in the initiation and progression of cardiomyopathy and associated heart failure. Experimental and human studies point to a critical role of cytoskeletal defects, with a clustering of mutations in genes encoding components of the Z disc and their interaction with titin and titin-associated proteins. Human mutations in titin, telethonin, and muscle LIM domain proteins (MLP, Cypher), have now been clearly implicated in the onset of human cardiomyopathy. In addition, Z disc proteins and the titin complex have recently been identified as an essential part of the cardiomyocyte biomechanical stretch sensor, suggesting that defects in cytoskeletal-dependent stress signaling pathways may be linked to the initiation and progression of human DCM. It will become critical to mechanistically link the complex Z disc and titin associated proteins that contribute to human heart failure. We have uncovered a number of new cardiac cytoskeletal-associated proteins that physically interact with titin, actin, and other components of the cardiac-stretch mediated responses. This proposal will capitalize on these novel cytoskeletal associated proteins, new mouse knockouts of these genes, new in vitro and in vivo assay systems that will allow a precise evaluation of the upstream and downstream signaling pathways that link them to key endpoints, and state-of-the-art transcriptional profiling and bioinformatics to identify downstream target genes. A direct evaluation of their mechanistic role in exacting a cause-effect relationship with stretch mediated responses will be evaluated by capitalizing on new assay systems in cultured cells, intact papillary muscle, and in the in situ heart to evaluate the role of these in stretch mediated responses. Accordingly, the Specific Aims of this proposal are: 1) To identify the mechanistic links between a gp130 dependent, biomechanical stress-inducible cytoskeletal associated protein (SprMA) and pathways for cardiomyocyte hypertrophy and survival; 2) To delineate the role of a titin-associated, stress inducible protein (CARP) in the transduction of downstream signals for cardiac hypertrophy during biomechanical stress; and 3) To define the role of myopalladin, a muscle restricted component of the CARP-titin complex, in biomechanical stress induced pathways for cardiac hypertrophy and cardiomyopathy.

描述（由申请人提供）：壁应力的慢性增加在心肌病和相关心力衰竭的启动和进展中起关键作用。实验和人类研究指出了细胞骨架缺陷的关键作用，在编码Z盘组分的基因中突变的聚类及其与TITIN和TITIN和TITIN相关蛋白的相互作用。现在，人类心肌病的发作清楚地涉及钛，链球菌和肌肉lim域蛋白（MLP，Cypher）中的人类突变。此外，Z盘蛋白和TITIN复合物最近被确定为心肌细胞生物力学拉伸传感器的重要组成部分，这表明细胞骨架依赖性应力信号传导途径的缺陷可能与人DCM的启动和进展有关。机械学上将复杂的Z光盘和钛相关的蛋白质链接起来，这将变得至关重要，这些蛋白会导致人体心力衰竭。我们发现了许多新的心脏细胞骨架相关蛋白，这些蛋白质与钛，肌动蛋白和心脏裂缝介导的反应的其他成分物理相互作用。该建议将利用这些新型的细胞骨架相关蛋白，这些基因的新老鼠敲除，新的体外和体内测定系统，这些系统将允许对上游和下游信号通路进行精确评估，以将它们链接到关键终点，以及先进的转录分析和生物潜在作用，并识别下游靶基因。通过在培养细胞，完整的乳头状肌肉以及原位心脏中评估这些作用在拉伸介导的反应中的作用，可以评估其与拉伸介导的反应的机械作用的直接评估，将评估与拉伸介导的响应的机械作用。因此，该提案的具体目的是：1）确定依赖性GP130，生物力学应激诱导的细胞骨架相关蛋白（SPRMA）与心肌细胞肥大和存活之间的机械联系； 2）描述与钛相关的应力诱导蛋白（CARP）在生物力学应力期间心脏肥大的下游信号中的作用； 3）为了定义肌甲基丁物蛋白的作用，肌甲基丁物蛋白伴侣的肌肉限制成分在生物力学应力诱导的心脏肥大和心肌病的途径中的作用。