Mechanisms of Posterior Heart Field Development

项目总结： 心脏由多种不同的心肌细胞类型组成，包括但不限于(有腔的和无腔的) 心肌细胞、心脏成纤维细胞、心外膜细胞、内皮/心内膜细胞 肌细胞，它们组织成不同的心脏结构，协调调节适当的心脏功能 并在全身循环。因为这些细胞类型单独的丢失或功能障碍或 联合作用可导致成人或先天性心脏病，最近越来越多的努力 致力于了解这些不同的心血管细胞类型是如何产生和发挥作用的，以便 开发潜在的人类心脏疗法。这样的努力不仅阐明了许多 心脏谱系，以及关键的信号信号和转录调节因子，而这些信号通路和转录调节因子又是最近 用于有效地引导各种非心脏来源，包括人类多能干细胞和人类 成纤维细胞转化为特定类型的心脏细胞，用于再生治疗。然而，心肌细胞类型是如何形成的 心脏流入道和发育相关的心外膜发育仍然不太确定，部分原因是 它们的起源不明。为了阐明这些问题，我们建议发现这些独特的心脏的起源 细胞类型，我们假设它们来自共同的心脏祖细胞来源，然后识别潜在的 调节其发育的信号机制。为此，我们将研究是否将外来者 NKX2.5心脏中胚层注定要成为心脏流入道心肌细胞和心外膜细胞，鉴定 指定心脏中胚层进入心脏前体细胞的信号通路，从而产生心脏流入道 心肌和心外膜，并研究这些发育机制是否 脊椎动物。

Project Summary: The heart consists of a multitude of diverse cardiac cell types, including but not limited to (chambered and non- chambered) cardiomyocytes, cardiac fibroblasts, epicardial cells, endothelial/endocardial cells and smooth muscle cells, which organize into distinct cardiac structures that coordinately regulate proper cardiac function and circulation throughout the body. Because loss or dysfunction of these cell types individually or combinatorially can lead to either adult or congenital heart diseases, increasing efforts have been recently devoted toward understanding how these diverse cardiovascular cell-types are created and function in order to develop potential human cardiac therapies. Such endeavors have illuminated not only the origins of many cardiac lineages but also key signaling cues and transcriptional regulators which in turn have been recently employed to efficiently direct various non-cardiac sources including human pluripotent stem cells and human fibroblasts into specific cardiac cell types for regenerative therapies. However, how cardiac cell types forming the cardiac inflow tract and the developmentally-related epicardium develop remains less certain in part due to their unclear origins. To shed light on these issues, we propose to discover the origins of these unique cardiac cell-types, which we posit derive from a common cardiac progenitor source, and then identify underlying signaling mechanisms that regulate their development. Toward this end, we will examine whether outlying Nkx2.5+ cardiac mesoderm is fated to become cardiac inflow tract cardiomyocytes and epicardial cells, identify signaling pathways that specify cardiac mesoderm into cardiac progenitors which create the cardiac inflow tract myocardium and epicardium and investigate whether these developmental mechanisms are conserved across vertebrates.