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，将胚胎干细胞（ESC）移植到衰竭或缺血的心脏组织中是有益的。这种益处背后的机制可能包括旁分泌因子和血管生成因子，以及通过分化 ESC 直接再生功能性心脏网络。拟议研究的主要总体目标是了解胚胎干细胞衍生的心肌细胞（ESC-CM）的植入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）的过度表达有助于 ESC-CM 掺入宿主心肌细胞网络并减轻 ESC-CM 的致心律失常性。申办者的实验室在心脏生理学方面拥有丰富的经验。最近，他们对干细胞修复缺血组织的再生潜力产生了兴趣，特别是可以确保安全有效的 ESC 植入的机制。在实现这一目标的过程中，成功地采用了 ESC 培养和心脏谱系定型的方法，并开发了 ESC 心肌移植的体外模型。在申办者实验室工作将使 PI 能够运用她之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。这次学习和培训机会将丰富 PI 作为一名科学家的能力，并为她的独立职业生涯做好准备。评估富含 ESC-CM 的心肌细胞网络的脉冲传播和兴奋性特性。解决富含 ESC-CM 的心肌细胞网络中异位心律失常的发生和发展。解决植入 ESC-CM 的心肌细胞网络中折返波的发生和起搏反应。测试新的假设，即 N-钙粘蛋白的过度表达将改善 ESC-CM 与宿主心肌的电学和机械连接，从而降低这些细胞的致心律失常性。

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.