REGULATORY FACTORS IN CARDIAC ADAPTATION

心肌肥厚是心肌对这两种因素的反应， 生理和代谢压力。 由急性 血流动力学超负荷和高血压引起特异性调节 在表达必需的心肌蛋白和伴随的 每单位心肌的收缩性降低。 不 这些蛋白质的异常表达 有助于改变收缩性能， 肥大和心力衰竭的发生。 识别和 细胞和亚细胞过程的表征， 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 的 观察到真核基因的表达是由 核调节因子参与了 转录复合体的形成与证据一起 血液动力学超负荷导致基因表达改变， 这是一个测试组织特异性调节 调节因子的出现是对与 肥厚 本报告概述了两个基本目标 建议：第一，确定具体的修改， 调节因子的组成负责激活 (or抑制）的候选基因，如肌球蛋白轻 链（MLC 2），这似乎是生物化学特征， 心脏肥大过程;第二，研究 MLC 2同种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 确定响应于以下的MLC 2特异性调节因子： 血流动力学过载并详细描述其在 肥大心肌中蛋白质表达的改变。 为了实现第二个目标，我们将制作变体MLC 2 同种型，在推定的功能结构域中具有确定的突变 并将这些变体替换为天然多肽。 蛋白质，以探索MLC 2的结构要求 在重构的肌动球蛋白复合物中发挥作用。 的 这些目标的实现将通过以下方式确定机制： 心脏工作负荷导致心肌细胞异常生成 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.