Endocardial mechanisms of cardiac trabeculation and septation

心脏小梁形成和分隔的心内膜机制

• 批准号: 8607702
• 负责人: Anthony B. Firulli
• 金额: $ 39万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-15 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8607702
• 关键词: BHLH Protein; Binding; Bioinformatics; Cardiac; Cardiac Output; Cell Lineage; Cells; Clinical; Common Ventricle; Congenital Abnormality; Congenital atresia of pulmonary valve; Data; Defect; Development; Electrophoretic Mobility Shift Assay; Embryo; Embryonic Development; Endocardium; Enhancers; Epicardium; Etiology; Exhibits; Functional RNA; Gene Expression; Genes; Growth; Heart; Helix-Turn-Helix Motifs; Hypoplastic Left Heart Syndrome; Knock-out; Lead; Left ventricular structure; Light; Lung; Mediating; Modeling; Molecular; Morphogenesis; Myocardial; Myocardium; Neural Crest Cell; Notch Signaling Pathway; Online Mendelian Inheritance In Man; Phenotype; Play; Population; Positioning Attribute; Pulmonary artery structure; Right atrial structure; Right ventricular structure; Role; Series; Signal Pathway; Signal Transduction; Stem cells; Structure; Testing; Tissues; Tricuspid Atresia; Venous; Ventricular; Ventricular septum; cardiogenesis; chromatin immunoprecipitation; congenital heart disorder; in vivo; insight; loss of function; migration; mutant; notch protein; novel; outcome forecast; programs; promoter; public health relevance; restoration; tissue culture

PROJECT SUMMARY/ABSTRACT Congenital heart disease (CHD) is the most common birth defect. Among various CHDs, single ventricle phenotypes resulting from altered ventricular morphogenesis have the poorest clinical prognoses and include Tricuspid Atresia (TA; OMIM# 605067), Double Inlet Left Ventricle (DILV), Pulmonary Atresia (OMIM# 265150), and Hypoplastic Left Heart Syndrome (OMIM# 241550, 614435). The single ventricle heart presents with a series circuit such that systemic venous return to the right ventricle and pulmonary arteries combined with the flow from the pulmonary venous return into the left ventricle and out to the body is incompatible with survival. Currently, there is a poor understanding of the molecular mechanisms and cellular etiology causative of the many forms of single ventricle CHD. The Basic helix-loop-helix factor Hand2 is expressed within the myocardium of the second heart field (SHF), epicardium, cardiac neural crest cells, and endocardium. Hand2 deletion results in E10.5 embryonic lethality due to the decreased growth in SHF-derived cardiac structures. Mef2c-Cre deletion of Hand2 from SHF progenitor cells, results in TA/ DILV phenotypes. We have recently determined that the observed single ventricle phenotypes are a direct consequence of Hand2 function in the endocardium. The function of Hand2 within the endocardium has not been investigated. Our findings lead to a novel hypothesis that signaling from the developing endocardium is critical in determining the position of the ventricular septum, which may potentially explain the etiology of some single ventricle CHDs. We outline a strategy to both characterize Hand2 endocardial function, to identify the direct upstream endocardial signaling network for Hand2, and the Hand2-downstream transcriptional targets within the developing endocardium. Defining these endocardial signaling pathways and developmental programs regulated by Hand2 will shed light on the cell etiology of single ventricle phenotypes and on the molecular programs controlling ventricular septation, thus expanding the understanding of ventricular wall trabeculation, and septal morphogenesis.

项目摘要/摘要 先天性心脏病（CHD）是最常见的先天缺陷。在各种CHD中，单脑室 心室形态发生变化引起的表型的临床预后最差，包括 三尖瓣闭锁（TA； OMIM＃605067），双入口左心室（DILV），肺闭锁（OMIM＃265150）， 和低塑性左心综合征（OMIM＃241550，614435）。单个心室心脏呈现 串联电路使得系统性静脉回到右心室和肺动脉结合 从肺静脉恢复到左心室并向外流到身体的流动与生存不相容。 目前，对分子机制和细胞病因的理解不足 多种形式的单脑室冠心。 基本的螺旋 - 环螺旋因子手2表示在第二心脏场（SHF）的心肌内， 心外膜，心脏神经rest细胞和心内膜。 HAND2删除导致E10.5胚胎致死性 由于SHF衍生的心脏结构的生长下降。 SHF的MEF2C-CRE删除了Hand2 祖细胞，导致TA/ DILV表型。我们最近确定观察到的单个 心室表型是心内膜中Hand2功能的直接结果。手的功能2 在内膜内尚未研究。我们的发现导致了一个新的假设，即来自 发育中的心内膜对确定心室隔膜的位置至关重要，这可能 有可能解释某些单个心室CHD的病因。我们概述了既表征的策略 Hand2心内膜功能，以识别Hand2的直接上游心内膜信号网络， 发育中的心内膜内的手2下游转录目标。定义这些心内膜 通过Hand2调节的信号通路和发展程序将阐明 单个心室表型和控制心室分隔的分子程序，从而扩大 对心室壁小径和间隔形态发生的理解。