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和血管生成因子，以及从分化的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。申请人将测试一种新的假设，即N-钙粘蛋白（一种关键的连接蛋白）的过表达促进ESC-CM掺入宿主心肌细胞网络并增强ESC-CM的促分化性。申办方实验室在心脏生理学方面具有丰富的经验。最近，他们开始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的ESC植入的机制。为了实现这一目标，成功地采用了ESC培养和心脏谱系定型的方法，并开发了ESC-心肌植入的体外模型。在申办方实验室工作将使PI能够应用其先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。这个学习和培训机会将丰富PI作为一个科学家，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。探讨ESC-CM富集的心肌细胞网络中异位心律失常的发生和发展。目的：探讨植入ESC-CM的心肌细胞网络中折返波的发生和起搏反应。为了验证新的假设，N-钙粘蛋白的过表达将改善ESC-CM与宿主心肌的电连接和机械连接，导致这些细胞的致炎性降低。

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.