Mechanisms of Posterior Heart Field Development

心后区发育机制

基本信息

批准号：
10669667
负责人：
Neil C Chi
金额：
$ 51.22万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-07-31
项目状态：
已结题

项目摘要

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.

项目概要：心脏由多种不同的心肌细胞类型组成，包括但不限于（心室细胞和非心细胞）室）心肌细胞、心脏成纤维细胞、心外膜细胞、内皮/心内膜细胞和平滑肌细胞肌肉细胞组织成不同的心脏结构，协调调节适当的心脏功能以及全身的循环。因为这些细胞类型单独或组合起来可能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开发潜在的人类心脏疗法。这些努力不仅阐明了许多心脏谱系，还有关键的信号传导线索和转录调节因子，而这些信号传导线索和转录调节因子最近又被用于有效引导各种非心脏来源，包括人类多能干细胞和人类将成纤维细胞转化为特定的心脏细胞类型以进行再生治疗。然而，心肌细胞类型如何形成心脏流入道和与发育相关的心外膜的发育仍然不太确定，部分原因是他们的起源不明。为了阐明这些问题，我们建议发现这些独特的心脏的起源我们假设细胞类型源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，我们将检查是否存在边远地区 Nkx2.5+心脏中胚层注定会成为心脏流入道心肌细胞和心外膜细胞，鉴定将心脏中胚层指定为心脏祖细胞的信号通路，从而形成心脏流入道心肌和心外膜，并研究这些发育机制是否在整个心肌和心外膜中保守脊椎动物。