INTEGRATED MECHANISMS OF CARDIAC MALADAPTATION

在这个互动和协同计划中提出的实验源于 以下问题：心脏细胞通过什么信号感觉到 负荷的变化以及如何处理信号来改变肌丝的活动？ 这些信号通过什么机制有效地使肌丝功能适应于 血流动力学负荷的变化以及为什么适应过程失败？这个 假设细胞应变的变化与细胞长度的变化有关， 单独或联合作用于细胞内钙离子或钙离子的变化 涉及蛋白质的磷基转移反应的级联改变 激酶C(PKC)，构成了信号转导机制。项目1(John Solaro/Anne Martin)是“心脏肌丝中的分子信号”。这 该项目研究了心肌肌丝的分子机制 以及它们的活性是如何被蛋白质亚型改变的 转换、肌节长度和蛋白质磷酸化。项目2(布伦达 是“机械活动和区域蛋白质合成”。这 该项目调查了以下各项之间联系的基本主题要素 机械功和应变、细胞内信号和蛋白质合成。 项目3(彼得·巴特里克)是“蛋白激酶C对心脏的影响” 使用转基因方法，这个项目的重点是 启动适应性和非适应性的主要信号通路 流程。项目4(Pieter DeTombe)是“从 从肥大到衰竭“，并解决了细胞机制的问题 从早期的补偿反应过渡到末期的反应 由心肌梗死引起的心力衰竭。这四个项目是 由行政、动物和生理学以及肌细胞和形态学支持 核心。这里提出的方案努力将提供重要的 理解机械和生化信号是如何从一种 血液动力学应激源，如高血压或心肌梗死 综合导致生理补偿和为什么失代偿 发生在心力衰竭。

Experiments proposed in this interactive and synergistic program arise from the following questions: What are the signals by which heart cells sense a change in load and how are signals processed to alter myofilament activity? By what mechanisms do the signals effectively adapt myofilament function to a change in hemodynamic load and why does the adaptation process fail? The hypothesis is that changes in cell strain associated with cell length changes, acting independently or in conjunction with changes in cellular Ca2+ or altered cascades of phosphoryl group transfer reactions involving protein kinase C (PKC), constitute the signaling mechanism. Project 1 (John Solaro/Anne Martin) is "Molecular Signaling in Cardiac Myofilaments." This project investigates the molecular mechanisms by which cardiac myofilaments are turned on and off and how their activity is modified by protein isoform switching, sarcomere length and protein phosphorylation. Project 2 (Brenda Russell) is "Mechanical Activity and Regional Protein Synthesis." This project investigates the essential thematic element of the linkages among mechanical work and strain, intracellular signals, and protein synthesis. Project 3 (Peter Buttrick) is "Effect of Protein Kinase C on Cardiac Hypertrophy." Using transgenic approaches, this project focuses on the primary signaling pathway that sets into motion the adaptive and maladaptive processes. Project 4 (Pieter deTombe) is "Mechanisms of Transition from Hypertrophy to Failure," and addresses the question of the cellular mechanisms of transition from compensatory responses in the early phase to end-stage heart failure induced by myocardial infarction. These four projects are supported by Administrative, Animal and Physiology, and Myocyte and Morphology Cores. The programmatic effort proposed here will provide important understanding of how mechanical and biochemical signals that arise from a hemodynamic stressor such as hypertension or myocardial infarction are integrated to give rise to physiological compensation and why decompensation occurs in heart failure.