The heart as a hemogenic organ

心脏作为造血器官

• 批准号: 8176553
• 负责人: Atsushi Nakano
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-05 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8176553
• 关键词: Aorta; Biological; Biomechanics; Blood Cells; Cardiac; Cardiovascular system; Cell model; Cells; Data; Development; Disease; Dorsal; Embryonic Development; Embryonic Heart; Endocardium; Endothelial Cells; Endothelium; Erythroid; Genes; Genetic; Genetic Programming; Goals; Heart; Heart Diseases; Hematological Disease; Hematopoiesis; Hematopoietic; In Situ; In Vitro; Lead; Life; Light; Link; Lymphocyte; Medullary Hematopoiesis; Molecular; Molecular Profiling; Mus; Muscle; Myelogenous; Myocardium; Organ; Pathogenesis; Patients; Physiological; Play; Process; Property; Pump; Reporting; Role; Site; Source; Testing; Tissues; Tube; Zebrafish; body system; c-myc Genes; cardiogenesis; embryonic stem cell; fly; hematopoietic tissue; hemodynamics; in vivo; novel; progenitor; programs; regenerative; spatiotemporal; transcription factor

DESCRIPTION (provided by applicant): The first functional organ system that develops during the mammalian life is the circulatory system, which consists of the heart tube, great vessels and hematopoietic tissues. The heart tube serves as the pump that starts to beat even before the formation of effective circulatory loop, and the dorsal aortae serve as conduits that form independently from the heart tube and link to it soon after. These two organs are structurally and molecularly similar in that they consist of outer muscular and inner endothelial/endocardial layers, and that each layer expresses many of the genes in common. Therefore, although derived from developmentally distinct origins, the heart tube and the dorsal aorta likely share similar genetic program during their formation. The third component of the circulatory system, the hematopoietic cells, arises from endothelial cells in dorsal aorta. This process is closely associated with the arterial identity of the aortic endothelium, such as the expression of arterial markers and the influence of biomechanical forces generated by the heartbeat. Interestingly, the endocardium in the heart tube shares all these molecular and physiological properties with aortic endothelilum. It has been suggested that the early cardiac progenitors express hematopoietic genes, and that cardiac and hematopoietic lineages are closely related in non-mammalian and embryonic stem cell models. In this proposal, we will examine the developmental role of the heart as a hematopoietic site. We specifically propose to characterize the spatiotemporal distribution and the multi-lineage differentiation potential of the putative hemogenic cells in the forming endocardium (Aim 1) and to examine the role of Nkx2.5 during the endocardial development (Aim 2). The overall goal of this proposal is to test the hemogenic activity of the heart. Discovery of a new role of the heart and a hidden source of blood cells will significantly enhance our understanding of the developmental program of cardio-vasculo-hematopoietic development. Clinically, extra-medullary hematopoiesis is often observed in patients with heart diseases and hematological disorders. The project will shed a light on the pathogenesis of this clinicopathological disease entity. PUBLIC HEALTH RELEVANCE: The close relationship between cardiac and hematopoietic lineages has been suggested in developmental and disease contexts, but it is still unclear the biological significance of the hematopoietic program in the heart. Here, we will uncover the novel role of the heart as a hemogenic organ.

描述（申请人提供）：哺乳动物一生中发育的第一个功能器官系统是循环系统，由心管、大血管和造血组织组成。心管充当泵，甚至在有效循环环形成之前就开始跳动，而背主动脉则充当独立于心管形成并很快与其连接的导管。这两个器官在结构和分子上相似，因为它们由外部肌肉层和内部内皮/心内膜层组成，并且每一层都表达许多共同的基因。因此，尽管心管和背主动脉的起源不同，但它们在形成过程中可能具有相似的遗传程序。循环系统的第三个组成部分是造血细胞，来自背主动脉的内皮细胞。这一过程与主动脉内皮的动脉特性密切相关，例如动脉标志物的表达以及心跳产生的生物力学力的影响。有趣的是，心管中的心内膜与主动脉内皮具有所有这些分子和生理特性。有人提出，早期心脏祖细胞表达造血基因，并且在非哺乳动物和胚胎干细胞模型中心脏和造血谱系密切相关。在本提案中，我们将研究心脏作为造血部位的发育作用。我们特别建议表征形成心内膜中推定造血细胞的时空分布和多谱系分化潜力（目标 1），并检查 Nkx2.5 在心内膜发育过程中的作用（目标 2）。该提案的总体目标是测试心脏的造血活性。心脏的新作用和血细胞的隐藏来源的发现将显着增强我们对心血管造血发育发育程序的理解。临床上，经常在患有心脏病和血液系统疾病的患者中观察到髓外造血。该项目将揭示这种临床病理疾病实体的发病机制。 公共卫生相关性：在发育和疾病背景下，心脏和造血谱系之间的密切关系已被提出，但仍不清楚心脏造血程序的生物学意义。在这里，我们将揭示心脏作为造血器官的新作用。