REGULATORY FACTORS IN CARDIAC ADAPTATION

心肌肥厚是心肌对两者的反应 身体和新陈代谢压力。急性心肌梗死引发的肥大 血流动力学超负荷和高血压引起特定的调节 在必需的心肌蛋白及其伴生物的表达中 单位心肌的收缩能力降低。它不是 明确这些蛋白质的异常表达到什么程度 有助于改变的收缩性能在 肥厚和心力衰竭的发作。身份识别和 控制细胞和亚细胞过程的特征 肌肉蛋白质的生物合成和功能是 了解这种心脏疾病的发病机制。这个 观察到真核基因的表达是由 参与活跃的核调控因子 转录复合体的形成与证据 血流动力学超负荷导致基因表达改变提供了 一种框架，用来测试组织特异性的调制 监管因素发生是对与以下相关的信号的响应 肥大。其中概述了两个基本目标 建议：首先，确定在 调节因子的组成负责激活 (或抑制)候选基因，如肌球蛋白光 链(MLC2)，这似乎是生化特征 心脏肥大过程；第二，研究心脏肥大过程 MLC2亚型在心肌功能适应中的作用 在肥大期间。第一个目标将通过以下方式实现 识别MLC2特定的调节因子，这些调节因子对 血流动力学过载及其在脑出血中的作用 肥厚心肌中蛋白质表达的改变。 对于第二个目标，我们将产生不同的MLC2 同种类型，在假定的功能结构域有明确的突变 多肽，并用这些变异体取代天然的 蛋白质，以探索MLC2的结构要求 在重组的肌动球蛋白复合体中发挥作用。这个 实现这些目标将通过以下方式定义机制(S) 哪种心脏工作负荷会导致心肌异常产生 蛋白质和改变心肌的机械性能。

Cardiac hypertrophy is the response of the myocardium to both physical and metabolic stress. Hypertrophy triggered by acute hemodynamic overload and hypertension elicit specific modulations in expression of essential myocardial proteins and a concomitant decrease in contractibility per unit of myocardium. It is not clear to what extent the anomalous expression of these proteins contribute to the altered contractile performance during hypertrophy and the onset of heart failure. Identification and characterization of cellular and sub-cellar processes that control the biosynthesis and function of muscle proteins is the key to understanding the pathogenesis of this cardiac disorder. The observations that expression of eukaryotic genes is mediated by nuclear regulatory factors which participate in active transcription complex formation taken together with the evidence that hemodynamic overload causes altered gene expression provides a framework in which to test whether modulations in tissue specific regulatory factors occur in response to signals associated with hypertrophy. There are two basis objectives outlined in this proposal: first, to establish that specific alterations in the composition of regulatory factors are responsible for activation (or repression) of a candidate gene, such as, for myosin light chain (MLC2), which appears to biochemically characterize the cardiac hypertrophic process; second, to investigate the contribution of MLC2 isotype in function adaption of the myocardium during hypertrophy. The first objective will be accomplished by identifying MLC2 specific regulatory factors which response to hemodynamic overload and characterizing in detail their role in altered expression of proteins in hypertrophied heart muscle. Towards the second objective, we shall produce variant MLC2 isotypes, with defined mutations in the putative functional domain of the polypeptide, and substitute these variants for the native protein in order to explore the structural requirements for MLC2 function in the reconstituted actomyosin complex. The accomplishment of these objectives will define the mechanism(s) by which cardiac workload leads to anomalous production of myocardial proteins and to altered mechanical performance of the heart muscle.