Hemogenic endocardium: contribution to the valvular tissue macrophages

造血心内膜：对瓣膜组织巨噬细胞的贡献

• 批准号: 9107302
• 负责人: Atsushi Nakano
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9107302
• 关键词: Ablation; Address; Adult; Affect; Apoptotic; Binding Sites; Biological; Blood; Blood Circulation; Blood Vessels; Bone Marrow; Cardiac; Cardiac development; Cardiovascular system; Cecum; Cells; Data; Data Set; Defect; Deformity; Deterioration; Development; Disease; Drosophila genus; Embryo; Embryonic Development; Endocardium; Functional disorder; Funding; Genes; Genetic; Genetic Predisposition to Disease; Growth; Heart; Heart Valves; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Homeostasis; Intestines; Label; Lead; Link; Live Birth; Mesenchyme; Molecular; Mus; Nucleic Acid Regulatory Sequences; Organ; Organism; Pathway interactions; Patients; Phagocytosis; Phylogenetic Analysis; Play; Population; Rest; Role; Signal Transduction; Site; Staging; Stream; System; Testing; Tissues; Travel; age related; base; fetal; in vivo; macrophage; mutant; notch protein; novel; overexpression; postnatal; programs; public health relevance; repaired; tool

 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.

 描述（由申请人提供）：心脏、血管和造血细胞的发育是相互关联的。通过先前的R21提案，造血细胞不仅仅是被动运输通过循环系统的，而且实质上参与了器官的发育和修复。 ，我们已经确定心内膜细胞产生造血细胞，这些造血心内膜细胞在小鼠胚胎的心内膜垫中富集并经历造血细胞。通过 Nkx2-5 依赖性方式实现心内膜造血转变的机制在物种间是保守的。然而，由于心内膜来源的造血细胞很少对出生后造血干细胞系统做出贡献，这一发现的生物学意义受到了阻碍。一个基本问题是为什么心脏在这个特定阶段需要在这个特定区域产生造血细胞，回答这个问题需要彻底了解造血细胞的分子机制和细胞分化。该提案利用特定的基因标记工具建立了关键的 Nkx2-5-Notch-Runx1 通路，这是一种源自造血心内膜细胞的新型组织巨噬细胞群，以及心内膜​​来源的组织巨噬细胞在形成中的先前未被认识到的作用。总之，该提议将为造血心内膜提供生物学意义，并证明造血心内膜不仅仅是系统发育的。先天性瓣膜异常影响着美国 1-2% 的活产儿，并且具有遗传倾向的患者更有可能出现与年龄相关的瓣膜缺陷。资助后，该提案将扩展我们的发现 血源性心内膜对先天性瓣膜异常的一种新疾病机制的影响。