The role of N-cadherin in stem cell engraftment to cardiac muscle

描述（由申请人提供）：多项研究表明胚胎干细胞（ESC）移植到衰竭或缺血性心脏组织中是有益的。这种益处背后的机制可能包括旁腺和血管生成因素，以及分化ESC直接再生功能性心脏网络。提出的研究的主要总体目标是了解胚胎干细胞来源的心肌细胞（ESC-CM）的移植如何影响宿主心脏组织的电生理特性。申请人将测试一个新的假设，即n -钙粘蛋白（一种关键的连接蛋白）的过表达促进了ESC-CM与宿主心肌细胞网络的结合，并减轻了ESC-CM的心律失常性。申办者的实验室在心脏生理学方面有丰富的经验。最近，他们对干细胞修复缺血组织的再生潜力感兴趣，特别是可以确保安全有效地植入ESC的机制。在实现这一目标的过程中，成功地采用了ESC培养和心脏谱系承诺的方法，并开发了ESC-心肌植入的体外模型。在赞助商的实验室工作将使PI能够应用她以前在分子生物学方面的专业知识，同时获得用于干细胞研究和心血管生理学的知识和技术。这次学习和培训的机会将丰富PI作为一名科学家，并为她独立的职业生涯做好准备。目的：观察ESC-CM富集的心肌细胞网络的脉冲传播和兴奋性特性。目的探讨ESC-CM富集的心肌细胞网络中异位性心律失常的发生和发展。探讨内皮细胞- cm移植心肌细胞网络中再入波的发生及起搏反应。为了验证N-cadherin过表达将改善ESC-CM与宿主心肌的电和机械连通性，从而降低这些细胞的心律失常性的新假设。

DESCRIPTION (provided by applicant): Multiple studies have shown that transplantation of embryonic stem cells (ESC) into failing or ischemic heart tissue is beneficial. The mechanisms behind such benefit may include paracrinal and angiogenic factors, as well as direct regeneration of a functional cardiac network from differentiating ESC. The main overall goal of the proposed studies is to understand how the engraftment of Embryonic Stem Cell-derived Cardiac Myocytes (ESC-CM) affects electrophysiological properties of the host cardiac tissue. The applicant will test a novel hypothesis that overexpression of N-cadherin, a key junctional protein, facilitates the incorporation of ESC-CM into the host cardiomyocyte network and alleviates ESC-CM arrhythmogenicity. The sponsor's lab has extensive experience in cardiac physiology. Recently they become interested in a regenerative potential of stem cells for repair of ischemic tissue, specifically mechanisms that can ensure safe and efficient ESC engraftment. En route to this goal, the methods of ESC culture and cardiac lineage commitment were successfully adapted, and in vitro model of ESC-cardiac muscle engraftment was developed. Working in the sponsor's lab will allow the PI to apply her previous expertise in molecular biology, while gaining knowledge and techniques that are used in stem cell research and cardiovascular physiology. This study and training opportunity will enrich the PI as a scientist and prepare her for an independent career. To assess the impulse propagation and excitability properties of cardiomyocyte networks enriched with ESC-CM. To address the occurrence and development of ectopic arrhythmias in the cardiomyocyte networks enriched with ESC-CM. To address the occurrence and pacing response of reentry waves in the cardiomyocyte networks engrafted with ESC-CM. To test the novel hypothesis that overexpression of N-cadherin will improve the electrical and mechanical connectivity of ESC-CM to the host myocardium, leading to decreased arrhythmogenicity of these cells.