Excitability Between Cardiac and Non-Cardiac Cells

心肌细胞和非心肌细胞之间的兴奋性

• 批准号: 7483675
• 负责人: Robin M Shaw
• 金额: $ 12.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7483675
• 关键词: Action Potentials; Affect; Arrhythmia; Behavior; Biology; Cardiac; Cardiac Muscle Contraction; Cardiac Myocytes; Cell Therapy; Cell Transplantation; Cell Transplants; Cells; Coculture Techniques; Color; Communication; Computer Simulation; Congestive Heart Failure; Connexin 43; Connexins; Coupling; Data; Electrophysiology (science); Embryo; Gap Junctions; Giant Cells; Goals; Heart failure; In Vitro; Ion Channel; Label; Lead; Lilium; Malignant - descriptor; Measures; Membrane; Modeling; Modification; Molecular; Muscle Cells; Muscle Fibers; Myoblasts; Myocardium; Patch-Clamp Techniques; Patients; Protein Overexpression; Proteins; Reporting; Research Personnel; Robin bird; Skeletal Myoblasts; Skeletal system; Staging; System; Therapeutic; Transplantation; Ventricular; Ventricular Arrhythmia; Work; base; cell type; design; embryonic stem cell; genetic manipulation; improved; insight; patch clamp; protein expression; simulation; skeletal transplantation; stem; tool

DESCRIPTION (provided by applicant): Cell transplantation of non-cardiac origin cells into myocardium is an attractive approach for restoring lost cardiac function, however, the electrical function of transplanted cells remains poorly understood. The transplanted cells are unlikely to communicate electrically as native cardiomyocytes do within the cardiac syncytium. In fact, the communication between cardiac and non-cardiac cells may be pro-arrhythmic, as preliminary reports have suggested. Thus, it is crucial to define the requirements for safe and effective electrical communication between transplanted non-cardiac cells and host cardiomyocytes. Cardiac excitability is determined by membrane ion channel activity and cell-to-cell coupling via cardiac gap junctions. Our preliminary studies indicate that primary cardiac cells can couple and electrically communicate with embryonic stem cell derived cardiomyocytes, but it is not clear that this communication is sufficient to be functional within a cardiac synctium. Our computer simulations have demonstrated that decreased gap junction coupling can lead to sustained ventricular arrhythmias. We are developing an in vitro experimental system in which labeled primary ventricular cardiomyocytes are co-cultured with embryonic stem cell derived cardiomyocytes and skeletal myocytes. We perform dual cell patch clamping to quantify the electrical communication between cell pairs and use these data with computer models to determine arrhythmogenic potential of regions of transplanted cells. As our preliminary data indicate that limited gap junction coupling can be arrhythmogenic, we will experimentally overexpress coupling protein and repeat assessment of coupling conductance and arrhythmogenesis. The proposed studies seek to establish the mechanisms of electrical communication between primary ventricular myocytes and putative candidates for cellular transplantation. The results will provide insight into the electrical impact of cells transplanted into ventricular myocardium, and lead to a therapeutic approach to decrease their arrhythmogenic behavior.

描述（由申请人提供）： 将非心脏来源的细胞移植到心肌中是恢复丧失的心脏功能的一种有吸引力的方法，然而，移植细胞的电功能仍然知之甚少。 移植的细胞不太可能像天然心肌细胞在心脏合胞体中那样进行电通讯。 事实上，正如初步报告所表明的那样，心脏和非心脏细胞之间的通讯可能会导致心律失常。 因此，确定移植的非心肌细胞与宿主心肌细胞之间安全有效的电通信的要求至关重要。 心脏兴奋性由膜离子通道活性和通过心脏间隙连接的细胞间耦合决定。 我们的初步研究表明，原代心肌细胞可以与胚胎干细胞衍生的心肌细胞耦合并进行电通信，但尚不清楚这种通信是否足以在心脏合胞体内发挥功能。 我们的计算机模拟表明，间隙连接耦合减少可导致持续性室性心律失常。 我们正在开发一种体外实验系统，其中标记的原代心室心肌细胞与胚胎干细胞衍生的心肌细胞和骨骼肌细胞共培养。 我们进行双细胞膜片钳来量化细胞对之间的电通讯，并将这些数据与计算机模型结合使用来确定移植细胞区域的致心律失常潜力。 由于我们的初步数据表明有限的间隙连接耦合可能导致心律失常，因此我们将通过实验过度表达耦合蛋白并重复评估耦合电导和心律失常发生。 拟议的研究旨在建立原代心室肌细胞和细胞移植候选细胞之间的电通讯机制。 研究结果将深入了解移植到心室心肌的细胞的电影响，并找到减少其致心律失常行为的治疗方法。