The Effects of Altered Contractility on Cardiac Myocyte Signaling and Hypertrophy

描述（由申请人提供）：心脏中的压力和容量超负荷导致心脏组织中的机械应力，进而导致心肌细胞表型改变。机械敏感性蛋白质如整合素被认为是机械应力和改变的表型之间的联系。许多研究已经着眼于施加于心肌细胞的外力如何影响整合素信号传导;然而，关于肌节产生的内部收缩力的变化如何影响整合素信号传导知之甚少。我们的长期目标是确定收缩力的变化如何影响心脏肥大。我们的一般假设是，心肌细胞中收缩蛋白产生的力激活整合素介导的信号转导，导致心肌肥厚中观察到的重塑，而不依赖于神经体液介导的信号或外部产生的牵拉。在这个提议中，我们将使用收缩性的小分子抑制剂来改变肌动蛋白-肌球蛋白力学，以确定它们对i）心肌细胞力学; ii）心肌细胞中的机械转导;和iii）心肌细胞肥大的影响。这些研究将为肌动蛋白-肌球蛋白力学如何影响心肌细胞信号传导和肥大提供重要的见解，并将有助于建立研究心肌病发病机制的分子基础的新技术。 公共卫生相关性：据估计，2010年有8100万美国人患有心血管疾病，心脏病是所有死亡的56%的因素。心力衰竭通常涉及心脏的扩大，这是由机械力触发的;然而，很少有人知道心脏产生的力如何影响其生长。在这项提案中，我们将使用新的方法来研究心肌收缩如何影响与心力衰竭相关的信号通路。

DESCRIPTION (provided by applicant): Pressure and volume overload in the heart causes mechanical stress in cardiac tissue, which in turn leads to altered phenotypes of cardiac myocytes. Mechanosensitive proteins such as integrins are thought to be the link between mechanical stress and altered phenotype. Many studies have looked at how external forces applied to cardiac myocytes influence integrin signaling; however, little is known about how changes in the internal contractile forces generated by sarcomeres affect integrin signaling. Our long term goal is to determine how changes in contractile forces influence cardiac hypertrophy. Our general hypothesis that the forces generated by contractile proteins in cardiac myocytes activate integrin mediated signal transduction leading to the remodeling seen in cardiac hypertrophy independent of neurohumoral mediated signals or externally generated stretch. In this proposal, we will alter actin-myosin mechanics using small molecule inhibitors of contractility to determine their effects on i) cardiac myocyte mechanics; ii) mechanotransduction in cardiac myocytes; and iii) cardiac myocyte hypertrophy. These studies will provide important insights into how actin-myosin mechanics influence cardiac myocyte signaling and hypertrophy and will help to establish new techniques for studying the molecular basis for the pathogenesis of cardiomyopathies. PUBLIC HEALTH RELEVANCE: In 2010 it is estimated that 81 million Americans have cardiovascular disease and heart disease is a factor in 56% of all deaths. The heart failure often involves enlargement of the heart, which is triggered by mechanical forces; however, little is known about how forces generated by the heart influence its growth. In this proposal, we will use novel approaches to study how cardiac muscle contraction influences signaling pathways associated with heart failure.