Intercellular Communication and Cardiac Arrhythmias

细胞间通讯和心律失常

• 批准号: 8257559
• 负责人: GREGORY E MORLEY
• 金额: $ 43.62万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-20 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8257559
• 关键词: Accounting; Adult; Arrhythmia; Attenuated; Biological; Cardiac; Cardiovascular Diseases; Cells; Cessation of life; Collagen; Connexins; Coupling; Development; Event; Extracellular Matrix; Fibroblasts; Fibrosis; Grant; Health; Heart; Heart failure; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Infarction; Injury; Maintenance; Maps; Membrane; Membrane Potentials; Molecular; Muscle Cells; Myocardial Infarction; Myocardial Ischemia; Myofibroblast; Optics; Organ; Phenotype; Potassium; Property; Rattus; Resolution; Rest; Techniques; Technology; Testing; Tissues; United States; Western World; Work; design; genetic profiling; improved; in vivo; intercellular communication; novel therapeutic intervention; prevent; research study; sudden cardiac death

PROJECT SUMMARY/ABSTRACT Cardiovascular disease is a major health problem in the western world and in the United States alone accounts for an estimated 500,000 deaths each year. The underlying mechanisms behind sudden cardiac death remain poorly understood. Many types of cardiovascular disorders including ischemic heart disease and heart failure are associated with extensive fibrosis. A critical event in the development of cardiac fibrosis is the transformation of fibroblasts into an active phenotype or myofibroblast. The question of whether fibroblast activation results in a different electrical phenotype that makes the heart susceptible to arrhythmic events remains to be explored. In this proposal, we will investigate the electrical phenotype of fibroblasts isolated from infarcted tissue. We will also work toward identifying new therapeutic approaches designed to alter the electrical phenotype of these cells. The overall aims of the grant are directed at determining whether preventing, delaying or limiting the activation of cardiac fibroblasts has potential beneficial antiarrhythmic effects. We have proposed three specific aims: Specific Aim 1 is to determine the potential of fibroblasts isolated from infarcted hearts to influence impulse propagation and arrhythmogenesis in heterocellular cultures of myocytes and adult fibroblasts. We hypothesize that cardiac injury alters the electrical phenotype of fibroblasts as assessed by high resolution optical mapping of heterocellular cultures. Specific Aim 2 is to determine the electrophysiological mechanisms of fibroblast activation. Here we hypothesize that the electrophysiological phenotype of fibroblasts isolated from infarcted tissue results from the combined effect of an increase in the level of intercellular coupling and a change in the resting membrane potential. Specific Aim 3 is to determine whether one of the pleiotropic effects of the HMG-CoA reductase inhibitors includes improving the conduction properties of infarcted tissue and rescuing the electrical phenotype of fibroblasts isolated from infarcted hearts. In this aim, we hypothesize that the anti-fibrotic properties of statins will attenuate the electrophysiological effects of fibroblast activation as assessed in isolated infarcted hearts and heterocellular cultures of myocytes and fibroblasts. To achieve these aims, we will utilize a combination of molecular biological and cellular electrophysiological techniques, as well as high resolution optical mapping technology at the organ and cellular levels.

项目总结/摘要 心血管疾病是西方世界的主要健康问题，仅在美国 估计每年有50万人因此死亡突发事件背后的潜在机制 心源性死亡仍然知之甚少。许多类型的心血管疾病，包括缺血性 心脏病和心力衰竭与广泛的纤维化有关。一个关键的事件， 心脏纤维化的发展是成纤维细胞转化为活性表型，或 肌成纤维细胞成纤维细胞活化是否导致不同的电表型的问题 使心脏易受心脏事件影响的原因仍有待探索。在本提案中，我们 将研究从梗塞组织分离的成纤维细胞的电表型。我们还将努力 旨在确定新的治疗方法，旨在改变这些电表型， 细胞补助金的总体目标是确定是否防止、推迟或 限制心脏成纤维细胞的活化具有潜在的有益抗肿瘤作用。我们有 提出了三个具体目标：具体目标1是确定分离自 梗死心脏影响的冲动传播和hemogenesis在异细胞培养， 肌细胞和成体成纤维细胞。我们假设心脏损伤改变了 通过异细胞培养物的高分辨率光学图谱评估成纤维细胞。具体目标2 是为了确定成纤维细胞激活的电生理机制。我们假设 从梗塞组织中分离的成纤维细胞的电生理表型是由 细胞间偶联水平的增加和静息细胞内蛋白质水平的改变的联合作用。 膜电位具体目标3是确定是否有一个多效性的影响， HMG-CoA还原酶抑制剂包括改善梗塞组织的传导性质， 挽救从梗塞心脏分离的成纤维细胞的电表型。为此，我们 假设他汀类药物的抗纤维化特性将减弱 在离体梗死心脏和肌细胞的异细胞培养物中评估的成纤维细胞活化 和成纤维细胞。为了实现这些目标，我们将利用分子生物学和 细胞电生理技术，以及高分辨率光学测绘技术， 器官和细胞水平。