INTEGRATED MECHANISMS OF CARDIAC MALADAPTATION

心脏适应不良的综合机制

• 批准号: 6746972
• 负责人: R John Solaro
• 金额: $ 185.87万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6746972
• 关键词: cardiac myocytes; muscle function; myocardium disorder

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.

在这个互动和协同计划中提出的实验来自于 以下问题：心脏细胞通过什么信号感知心脏活动？ 负荷的变化以及如何处理信号以改变肌丝活性？ 信号通过什么机制有效地使肌丝功能适应 血流动力学负荷的变化以及自适应过程失败的原因？ 的 假设是细胞株的变化与细胞长度的变化相关， 独立作用或与细胞内Ca 2+变化联合作用，或 涉及蛋白质的磷酰基转移反应的改变级联 蛋白激酶C（PKC）是其信号转导机制。 项目1（约翰 Solaro/Anne Martin）是“心脏肌丝中的分子信号传导。“这 该项目研究了心脏肌丝 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 罗素）是“机械活动和区域蛋白质合成。“这 项目调查了以下方面之间联系的基本专题要素： 机械功和应变、细胞内信号和蛋白质合成。 项目3（Peter Buttrick）是“蛋白激酶C对心脏的影响” 肥厚“利用转基因方法，该项目的重点是 启动适应性和适应不良的主要信号通路 流程. 项目4（Pieter deTombe）是“从 肥大到衰竭”，并解决了细胞机制的问题， 从早期阶段的补偿反应过渡到末期阶段 心肌梗塞引起的心力衰竭。 这四个项目是 由管理、动物和生理学以及肌细胞和形态学支持 丹 这里提出的方案努力将提供重要的 了解机械和生物化学信号是如何产生的， 血液动力学应激源如高血压或心肌梗塞， 综合起来产生生理补偿，为什么代偿失调 发生在心力衰竭时