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（通过应用程序提供）：心脏，血管和造血的发展是相互联系的。造血细胞不仅是通过电路系统被动运输的，而且基本上涉及器官的发展和修复。通过先例的R21提案，我们确定心内膜细胞会产生造血细胞。这些血肿的心内膜细胞富含小鼠胚胎的缓冲心内膜，并通过NKX2-5-依赖性方式进行心脏心脏 - 毛虫过渡。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了以下事实的阻碍：内膜衍生的造血细胞很少有助于骨髓的产后造血干细胞系统。一个基本的问题是，为什么心脏需要在该特定阶段在该特定区域产生造血细胞。回答此任务需要彻底了解血源性心内膜的分子机制和细胞分化。该提案利用特定的遗传标记工具来建立关键的NKX2-5- NOTCH-RUNX1途径，源自植物性心内膜细胞的新型组织巨噬细胞种群，以及先前未批准的心脏来源衍生的组织巨噬细胞在心脏瓣膜形成中的作用。总之，该提案将为血源性心内膜提供生物学意义，并证明，血词内膜心脏不仅是肠道盲肠的系统发育性残留物，而且是必不可少的成分，它在器官功能中起着重要作用。先天性瓣膜异常影响美国的活产1-2％，遗传倾向的患者更有可能发展与年龄相关的瓣膜缺陷。如果资助，该提案将扩大我们的发现 先天性瓣膜异常的新型疾病机制的血液中心心内膜。