Patterning by Invasive Mesenchyme in the Embryonic Heart

我们计划项目的中心假设是，主要负责正常和畸形心脏发育的机制并不完全是心源性中胚层所固有的。提出了连续波侵袭间充质所携带的启发性线索。研究认为，脊椎动物心脏从简单的蠕动血管到复杂的多腔泵的显著转变，关键在于一连串侵袭的间质所携带的具有启发性的线索。这些间充质细胞迁移的来源是多样的，包括体腔间皮(心外膜前来源)和神经管(神经脊)。该计划旨在评估这些迁移在协调心血管模式形成的多个方面的影响，包括房室传导系统发育、心外膜形成、流出道形成和冠状动脉床的部署。项目I的主题是人类房室传导系统中正常和异常电连接的遗传学。这里的一个关键假设是，Nkappax2.5突变导致细胞向传导系统募集的异常模式。项目二将研究侵袭性、心外膜来源的间质(EPDCs)和WNT信号在房室传导系统中协调模式形成中的作用。这项研究的一个主要假设是，EPDCs与胚胎心肌之间的相互作用与专门化传导心肌募集相关基因程序的诱导密切相关，与专门化传导心肌募集相关基因程序的诱导密切相关(例如连接蛋白40/42和NKX2.5)。在项目III中，研究了神经脊和心外膜来源细胞之间的缝隙连接通讯的作用。这里的目标是确定细胞内对话如何协调这些队列的运动性，并最终影响心外膜上皮-间充质转化的流出诱导。这个项目的总体目标是启动这些间充质细胞在心脏内的侵袭潜力。该计划整合了多种最先进的方法(包括转基因基因打靶、基因芯片阵列筛选、超快动态成像和人类亲属的遗传连锁分析)，并建立了研究人员的专业知识，以创建一个独特的研究环境，以确定决定人类心血管系统结构畸形的潜在机制。

The central hypothesis of our Program Project is that the mechanisms primarily responsible for normal and malformed heart development are not wholly intrinsic to cardiogenic mesoderm. It is proposed that instructive cues carried by successive waves of invading mesenchyme. It is proposed that instructive cues carried by successive waves of invading mesenchyme are key to the remarkable transformation of the vertebrate heart from a simple, peristaltic vessel to a complex, multi-chambered pump. The sources from which these mesenchymal cells migrate are diverse and include the coelomic mesothelium (source of pro-epicardium) and the neural tube (neural crest). The Program seeks to evaluate the impact of these migrations in orchestrating multiple facets of cardiovascular pattern formation including atrioventricular (AV) conduction system development, epicardiogenesis, outflow tract formation and deployment of the coronary arterial bed. The theme of Project I is the genetics of normal and abnormal electrical linkage in the human AV conduction system. A key hypothesis here is that Nkappax2.5 mutation results in abnormal patterns of cellular recruitment to the conduction system. Project II will investigate the role of invasive, epicardial-derived mesenchyme (EPDCs) and WNT-signaling in orchestrating pattern formation in the AV conduction system. A principal hypothesis in this study is that interaction between EPDCs and embryonic myocardium is intimately tied to the induction of gene programs associated with recruitment of specialized conductive myocardium is intimately tied to the to the induction of gene programs associated with recruitment of specialized conductive myocardium (e.g. Connexin 40/42 and Nkx2.5). In Project III, the role of gap junctional communication between neural crest and epicardial-derived cells is studied. The goal here is to determine how intracellular dialogue coordinates the motility of these cohorts and ultimately influences outflow induction of epithelial- mesenchymal transformation at the epicardium. The overall goal of this project is to initiate the intra-cardiac invasive potential of these mesenchymal cells. This Program integrates diverse and state-of-the-art methodologies (including transgenic gene targeting, gene microchip array screening, ultrarapid dynamic imaging and genetic linkage analysis of human kindreds) and established investigator expertise to create a unique research environment to determine the underlying mechanisms that determine structural malformation of the human cardiovascular system.