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）：室壁应力的慢性增加在心肌病和相关心力衰竭的发生和进展中起关键作用。实验和人体研究指出细胞骨架缺陷的关键作用，与Z盘的基因编码组件及其与肌联蛋白和肌联蛋白相关蛋白的相互作用的突变的集群。肌联蛋白、肌联蛋白和肌肉LIM结构域蛋白（MLP，Cypher）的人类突变现在已明确与人类心肌病的发病有关。此外，Z盘蛋白和肌联蛋白复合物最近已被确定为心肌细胞生物力学拉伸传感器的重要组成部分，这表明细胞膜依赖性应激信号通路的缺陷可能与人类DCM的起始和进展有关。将复杂的Z盘与导致人类心力衰竭的肌联蛋白相关蛋白机械地连接将变得至关重要。我们已经发现了一些新的心肌细胞膜相关蛋白，它们与肌联蛋白、肌动蛋白和心脏牵张介导的反应的其他组分发生物理相互作用。该提案将利用这些新的细胞骨架相关蛋白，这些基因的新小鼠敲除，新的体外和体内测定系统，该系统将允许精确评估将其与关键终点联系起来的上游和下游信号传导途径，以及最先进的转录谱分析和生物信息学来识别下游靶基因。将通过利用培养细胞、完整乳头肌和原位心脏中的新测定系统来评估它们在与牵张介导的反应之间的因果关系中的机械作用的直接评估，以评估它们在牵张介导的反应中的作用。因此，本研究的具体目的是：1）确定gp 130依赖的、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途径之间的机制联系; 2）阐明肌联蛋白相关的、应激诱导蛋白（CARP）在生物力学应激过程中心肌肥大下游信号转导中的作用;和3）确定肌球蛋白（myopalladin），CARP-肌联蛋白复合物的肌肉限制性组分，在生物力学应力诱导的心肌肥大和心肌病途径中的作用。