Hemogenic endocardium: contribution to the valvular tissue macrophages

 描述（申请人提供）：心脏、血管和造血的发育是相互联系的。造血细胞不仅仅是被动地通过循环系统运输的乘客，而是实质性地参与器官的发育和修复。通过先前的R21建议，我们已经确定内皮细胞产生造血细胞。这些生血内皮细胞在小鼠胚胎的垫状内皮细胞中富集，并通过Nkx 2 -5依赖的方式经历心内膜-造血转化。这种机制在物种之间是保守的。然而，这一发现的生物学意义受到心内膜来源的造血细胞很少对骨髓中的出生后造血干细胞系统有贡献的事实的阻碍。一个根本的问题是为什么心脏需要在这个特定的阶段在这个特定的区域产生造血细胞。要回答这个问题，需要深入了解生血内皮细胞的分子机制和细胞分化。该提议利用特异性遗传标记工具来建立关键的Nkx 2 -5-Notch-Runx 1通路，一种源自生血内皮细胞的新型组织巨噬细胞群体，以及心内膜来源的组织巨噬细胞在心脏瓣膜形成中的先前未被认识的作用。总之，这一建议将提供一个生血内皮细胞的生物学意义，并证明生血内皮细胞不仅是一个类似肠盲肠的再生残余物，而是一个不可或缺的组成部分，在器官功能中起着重要作用。先天性瓣膜异常影响美国1-2%的活产婴儿，而有遗传倾向的病人更容易患上与年龄有关的瓣膜缺陷。如果得到资助，这项提议将扩大我们的发现 一种新的先天性瓣膜畸形的发病机制。

 DESCRIPTION (provided by applicant): The development of cardiac, vascular and hematopoietic is mutually linked. The hematopoietic cells are not just passengers passively transported through the circulatory system, but substantially involved in the development and repair of the organs. Through the precedent R21 proposal, we have established that endocardial cells give rise to hematopoietic cells. These hemogenic endocardial cells are enriched in the cushion endocardium in mouse embryos and undergo endocardial-hematopoietic transition via Nkx2-5- dependent manner. This mechanism is conserved among species. However, biological significance of this discovery has been hampered by the fact that the endocardially-derived hematopoietic cells rarely contribute to the postnatal hematopoietic stem cell system in the bone marrow. A fundamental question is why the heart needs to generate hematopoietic cells in this specific region at this specific stage. Answer to this questio requires thorough understanding of the molecular mechanism and cellular differentiation of the hemogenic endocardium. This proposal take advantage of specific genetic labeling tool to establish a pivotal Nkx2-5- Notch-Runx1 pathway, a novel tissue macrophage population originating from hemogenic endocardial cells, and a previously unappreciated role of endocardially-derived tissue macrophages in the formation of the cardiac valves. Together, this proposal will provide a biological significance to hemogenic endocardium, and demonstrate that the hemogenic endocardium is not merely a phylogenetical remnant like intestinal cecum but an indispensable component that plays a significant role in the organ function. Congenital valvular anomaly affects 1-2% of live births in the U.S., and patients with genetic predisposition are more likely to develop age- related valvular defects. If funded, this proposal will extend our discovery of hemogenic endocardium to a novel disease mechanism of congenital valvular anomalies.