CYTOSKELETON AND CONTRACTILE DYSFUNCTION IN HYPERTROPHY

肥大症中的细胞骨架和收缩功能障碍

• 批准号: 6631281
• 负责人: GEORGE COOPER
• 金额: $ 29万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6631281
• 关键词: beta adrenergic receptor; cardiac myocytes; cytoskeletal proteins; disease /disorder model; extracellular matrix; genetic regulation; genetically modified animals; heart contraction; hypertrophic myocardiopathy; laboratory mouse; microfilaments; microtubule associated protein; microtubules; muscle proteins; protein biosynthesis; protein isoforms; protein structure function; tubulin

The initial goals of this project were to determine whether cytoskeletal alterations have a role in the contractile dysfunction of hypertrophied myocardium, and if so, what is their nature, their locus, and their cause. Important accomplishments have been 1) the demonstration of microtubule- based contractile dysfunction in cardiocytes from the hypertrophied and failing RV and LV, 2) extension of these findings to isolated tissue and to the intact heart, 3) biophysical characterization of the etiology of the microtubule-based contractile dysfunction, 4) the finding that this pathophysiological mechanism is tightly restricted to pressure overload- induced hypertrophy in which wall stress is increased, 5) the demonstration that microtubules are the only major extra-myofilament cytoskeletal protein so affected, 6) the finding that this phenomenon is based both on increased tubulin, and thus microtubules, and on increased stability of the microtubules once formed, 7) the finding that the major cardiac microtubule-stabilizing protein is markedly up-regulated in pressure overload cardiac hypertrophy, 8) the finding that transcriptional upregulation of two minor beta-tubulin isoforms during hypertrophy, which we found to mimic the developmental regulation of these genes, accounts for the increase in beta-tubulin, and 9) the demonstration that one of these isoforms may act synergistically with MAP 4 to stabilize microtubules in pressure overload cardiac hypertrophy. The first goal of the work proposed is to reduce the correlative relationship between microtubule network densification and cardiac contractile dysfunction to a cause-and-effect relationship via direct genetic manipulation of microtubule stability and via an exploration of the role of altered expression of genes encoding microtubule and microtubule-associated proteins found to date. The second goal is to extend this investigation from microtubule effects on cardiocyte constitutive properties to a consideration of more specific microtubule-dependent effects on cardiocyte constitutive properties to a consideration of more specific microtubule- dependent effects on the hypertrophied cell, and explicitly, a consideration of any role of increased density of the cardiocyte microtubule network in the beta-adrenergic receptor desensitization characteristic of cardiac hypertrophy.

该项目的最初目标是确定细胞骨架是否 改变在肥厚的收缩功能障碍中起作用 心肌，如果是的话，它们的性质、位置和原因是什么。 重要的成就是1）微管的演示- 心肌细胞肥大和收缩功能障碍 RV 和 LV 失败，2）将这些发现扩展到孤立的组织和 对于完整的心脏，3）病因学的生物物理特征 基于微管的收缩功能障碍，4）发现 病理生理机制严格限制于压力超负荷 诱发肥大，其中壁应力增加，5) 证明微管是唯一主要的肌丝外 细胞骨架蛋白受到如此影响，6）发现这种现象是 基于增加的微管蛋白和微管，以及增加的 微管一旦形成的稳定性，7）发现主要 心脏微管稳定蛋白显着上调 压力超负荷心脏肥大，8）转录的发现 肥大期间两种次要 β-微管蛋白亚型的上调， 我们发现可以模仿这些基因的发育调节 β-微管蛋白的增加，以及 9) 证明其中之一 这些亚型可能与 MAP 4 协同作用以稳定 压力超负荷心脏肥大中的微管。第一个目标是 建议的工作是减少之间的相关关系 微管网络致密化和心肌收缩功能障碍 通过直接基因操作建立因果关系 微管稳定性并通过探索改变的作用 编码微管和微管相关基因的表达 迄今为止发现的蛋白质。第二个目标是扩大调查范围 从微管对心肌细胞构成特性的影响到 考虑对心肌细胞更具体的微管依赖性影响 考虑更具体的微管的构成特性 对肥大细胞的依赖效应，并且明确地， 考虑心肌细胞密度增加的任何作用 β-肾上腺素能受体脱敏中的微管网络 心脏肥大的特征。