The Effects of Altered Contractility on Cardiac Myocyte Signaling and Hypertrophy

收缩力改变对心肌细胞信号传导和肥大的影响

基本信息

批准号：
8112353
负责人：
Jonathan E. Baker
金额：
$ 20.99万
依托单位：
UNIVERSITY OF NEVADA RENO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8112353
关键词：
Actins Adhesions Adult Affect American Attenuated Binding Cardiac Cardiac Muscle Contraction Cardiac Myocytes Cardiomegaly Cardiomyopathies Cardiovascular Diseases Cells Cessation of life Characteristics Collagen Contractile Proteins Data Dilated Cardiomyopathy Disease Excision Exhibits Extracellular Matrix Familial Hypertrophic Cardiomyopathy Fluorescence Microscopy Focal Adhesions Generations Glass Goals Growth Heart Heart Diseases Heart Hypertrophy Heart failure Hypertrophy Immunofluorescence Microscopy Integrin Signaling Pathway Integrins Intercalated disc Laminin Link Measurement Measures Mechanical Stress Mechanics Mediating Microspheres Molecular Muscle Cells Muscle Fibers Mutation Myocardium Myosin ATPase Neonatal Pathogenesis Pattern Phenotype Physiological Positioning Attribute Proteins Rattus Sarcomeres Signal Pathway Signal Transduction Siloxanes Stretching Structure Talin Techniques Testing Time Tissues Ventricular Width base blebbistatin body system inhibitor/antagonist insight molecular marker nanometer novel strategies particle pressure response small molecule

项目摘要

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.

描述（由申请人提供）：心脏中的压力和体积超负荷会导致心脏组织的机械应力，进而导致心肌细胞的表型改变。机械敏感蛋白（例如整联蛋白）被认为是机械应力和改变表型之间的联系。许多研究研究了外力如何应用于心肌细胞，影响整联蛋白信号传导。但是，关于肉瘤产生的内部收缩力的变化如何影响整联蛋白信号传导，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联蛋白介导的信号转导，从而导致在心脏肥大中看到的重塑，而与神经肿瘤介导的信号无关或外部产生的拉伸。在此提案中，我们将使用小分子抑制剂来改变肌动蛋白肌球蛋白力学，以确定其对i）心肌细胞力学的影响； ii）心肌细胞的机械转导； iii）心肌肥大。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，并有助于建立新的技术来研究心肌病发病的分子基础。公共卫生相关性：2010年，据估计，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。 The heart failure often involves enlargement of the heart, which is triggered by mechanical forces;但是，关于心脏产生的力如何影响其生长的力量知之甚少。在此提案中，我们将使用新颖的方法研究心肌收缩如何影响与心力衰竭相关的信号通路。