CYTOSKELETON AND CONTRACTILE DYSFUNCTION IN HYPERTROPHY

这个项目的最初目标是确定细胞骨架是否 改变在肥厚性心肌收缩功能障碍中的作用 心肌，如果是，他们的性质，他们的轨迹，他们的原因。 重要的成果是1)微管的演示-- 肥厚型和非肥厚型心肌细胞的基础收缩功能障碍 失败的RV和LV，2)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)这一发现 病理生理机制严格受限于压力超负荷- 室壁应力增加的诱导肥厚，5) 证明微管是唯一主要的肌外肌丝 细胞骨架蛋白受到如此影响，6)发现这种现象是 既基于微管蛋白的增加，也基于微管的增加 一旦形成微管的稳定性，7)发现主要的 心脏微管稳定蛋白显著上调 压力超负荷心肌肥厚，8)发现转录 肥厚过程中两种次要的β-微管蛋白亚型上调 我们发现模仿这些基因的发育调节，帐户 对于β-微管蛋白的增加，以及9)其中之一的证明 这些异构体可能与MAP 4协同作用以稳定 压力超负荷心肌肥厚中的微管。的第一个目标 本文提出的工作就是减少两者之间的相关关系 微管网络致密化与心脏收缩功能障碍 通过直接的基因操作产生的因果关系 微管稳定性和通透性改变的作用探讨 微管及微管相关编码基因的表达 到目前为止发现的蛋白质。第二个目标是扩大这项调查 从微管对心肌细胞组成特性的影响到 考虑更具特异性的微管依赖对心肌细胞的影响 考虑更具体的微管的本构特性- 对肥大细胞的依赖作用，而且明确地说， 考虑增加心肌细胞密度的任何作用 微管网络在β肾上腺素能受体脱敏中的作用 以心肌肥大为特征的。

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.