The heart as a hemogenic organ

心脏作为造血器官

基本信息

批准号：
8320070
负责人：
Atsushi Nakano
金额：
$ 19.25万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-05 至 2014-05-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：在哺乳动物生命期间开发的第一个功能器官系统是循环系统，它由心管，伟大的血管和造血组织组成。心管作为泵，甚至在有效循环环形成之前就开始跳动，而背主动脉作为导管，它们是独立于心脏管并链接到它的导管。这两个器官在结构和分子上非常相似，因为它们由外肌和内皮内皮/内膜层组成，并且每个层都表达许多共同的基因。因此，尽管心管和背主动脉在形成过程中可能具有相似的遗传程序，但源自发育不同的起源。循环系统的第三个成分是造血细胞，是由背主动脉内皮细胞产生的。该过程与主动脉内皮的动脉认同密切相关，例如动脉标记的表达以及心跳产生的生物力学力的影响。有趣的是，心脏管中的心内膜具有与主动脉内皮的所有这些分子和生理特性。已经提出，早期的心脏祖细胞表达造血基因，并且心脏和造血谱系在非哺乳动物和胚胎干细胞模型中密切相关。在此提案中，我们将研究心脏作为造血部位的发育作用。我们特别建议表征假定的血液生成细胞在形成内膜内的时空分布和多轮分化潜力（AIM 1），并检查内膜发育过程中NKX2.5的作用（AIM 2）。该提议的总体目标是测试心脏的生气活性。发现心脏的新作用和隐藏的血细胞来源将显着增强我们对心脉 - 静脉 - 山脉 - 山摩托学发育的发展计划的理解。在临床上，在心脏病和血液学疾病的患者中经常观察到高管外造血。该项目将阐明该临床病理疾病实体的发病机理。