MECHANISMS FOR LOAD INDUCTION OF HYPERTROPHY

这项拨款提案的总体目标是确定以下哪些要素 血流动力学负荷是心肌细胞的主要力学决定因素 质量，并定义细胞内信号机制的耦合 血流动力学导致肥大反应。三个假设将是 检测：1)正常的心肌细胞结构和质量是直接和持续的 正常蜂窝负载环境的结果，而不是固定的属性 这种正常的负荷环境可以在 体外细胞培养模型，2)体外细胞培养过程中所产生的活力 心肌细胞在收缩(后负荷)时的被动休息 肌节长度(预负荷)和心肌细胞收缩频率 (张力-时间指数)是心肌细胞的主要机械决定因素 质量，以及3)这些决定因素不同地调节心肌细胞质量 通过整合素依赖的细胞信号通路耦合改变 血流动力学负荷对心肌细胞结构和质量的调节作用。这些 假设将通过三个具体目标进行检验：1)定义 整合素介导的心肌细胞黏附在维持 成年哺乳动物心肌细胞的长期原代培养 建立心肌细胞包埋在凝胶基质中的体外模型 紧密模拟体内合成结构的环境 心肌，2)定义主要的动态力学决定因素 心肌细胞质量，以及3)定义这些主要的 心肌细胞质量的机械决定因素与细胞 将机械输入传递到心肌细胞的信号通路 肥大反应。

The overall goal of this grant proposal is to identify which elements of hemodynamic load are the primary mechanical determinants of cardiocyte mass and to define the intracellular signaling mechanisms which couple hemodynamic lead to the hypertrophic response. Three hypothesis will be tested: 1) normal cardiocyte structure and mass are the direct and ongoing result of a normal cellular loading environment and not a fixed property of the cardiocyte; this normal loading environment can be recreated in an in vitro cell culture model, 2) the active force developed and bourne by the cardiocyte during contraction (after-load), the passive resting sarcomere length (pre-load), and the cardiocyte contraction frequency (tension-time index) are the primary mechanical determinants of cardiocyte mass, and 3) these determinants differentially regulate cardiocyte mass through integrin-dependent cellular signalling pathways couple alterations in hemodynamic load to regulation of cardiocyte structure and mass. These hypothesis will be tested via three specific aims: 1) define the role that integrin-mediated cardiocyte adhesion plays in the ability to maintain adult mammalian cardiocytes in long-term primary culture using our newly developed in vitro model in which cardiocytes are embedded in a gel matrix environment which closely mimics the in vivo composite structure of the myocardium, 2) define the primary dynamic mechanical determinants of cardiocyte mass, and 3) define the mechanisms by which these primary mechanical determinants of cardiocyte mass are coupled to the cellular signaling pathways which transduce mechanical input into the cardiocyte hypertrophic response.