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)是最常见的出生缺陷。在各种CHD中，单心室 由心室形态发生改变引起的表型临床预后最差，包括 三尖瓣闭锁(TA；OMIM#605067)，左心室双入口(DILV)，肺闭锁(OMIM#265150)， 和左心发育不全综合征(OMIM#241550,614435)。单心室心脏表现为 串联回路使全身静脉回流到右心室和肺动脉相结合 从肺静脉回流到左心室和外流到身体是不相容的生存。 目前，对该病的分子机制和细胞病因学了解甚少。 多种形式的单心室先心病。 基本螺旋-环-螺旋因子Hand2在第二心场(SHF)的心肌内表达， 心外膜、心脏神经脊细胞和心内膜。Hand2缺失导致E10.5胚胎死亡 这是由于SHF来源的心脏结构生长减少。MEF2C-CRE从SHF中删除Hand2 祖细胞，导致TA/DILV表型。我们最近确定了观察到的单曲 心室表型是心内膜中Hand2功能的直接结果。Hand2的功能 心内膜内还没有被研究过。我们的发现导致了一种新的假设，即信号来自 发育中的心内膜对确定室间隔的位置至关重要，这可能 有可能解释一些单心室先心病的病因学。我们勾勒出一种策略，既可以描述 Hand2心内膜功能，以确定Hand2的直接上游心内膜信号网络，以及 Hand2-发育中的心内膜内的下游转录靶点。定义这些心内膜 Hand2调控的信号转导途径和发育程序将有助于阐明细胞病因学 单心室表型和控制室间隔的分子程序，从而扩大 对室壁小梁形成和间隔形态发生的认识。