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，他们的本性，基因座和原因是什么。 重要的成就是1）微管的演示 来自肥厚的心细胞的基于基于的收缩功能障碍， RV和LV失败，2）将这些发现扩展到孤立的组织和 完整的心脏，3）病因的生物物理特征 基于微管的收缩功能障碍，4）发现这一点 病理生理机制紧密地限于压力超负荷 - 诱导的肥大，其中壁应力增加，5） 证明微管是唯一主要的胸膜外丝 细胞骨架蛋白如此受影响，6）发现这种现象是 基于微管蛋白增加，因此是基于微管，并增加 微管的稳定性一旦形成，7） 心脏微管稳定蛋白在 压力超负荷心脏肥大，8）转录的发现 在肥大期间的两个次要β-微管蛋白同工型的上调，这 我们发现模仿了这些基因的发育调控，说明了 为了增加β-微管蛋白，以及9）证明之一 这些同工型可能与地图4协同作用以稳定 压力过载心脏肥大中的微管。第一个目标 提出的工作是减少相关关系 微管网络致密和心脏收缩功能障碍 通过直接遗传操纵的因果关系 微管稳定性以及通过探索改变的作用 编码微管和微管相关的基因的表达 迄今为止发现的蛋白质。第二个目标是扩展此调查 从微管对心细胞本构特性的影响到A 考虑更具体的微管对心细胞的影响 构成性特性，以考虑更具体的微管 对肥厚细胞的依赖性作用，明确的A 考虑到心脏细胞密度增加的任何作用 β-肾上腺素能受体脱敏的微管网络 心脏肥大的特征。