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: 8901593
• 负责人: Anthony B. Firulli
• 金额: $ 3.02万
• 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/8901593
• 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; Health; 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; restoration; tissue culture

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：先天性心脏病（CHD）是最常见的出生缺陷。在各种CHD中，由心室形态发生改变引起的单心室表型具有最差的临床表现，包括三尖瓣闭锁（TA; OMIM# 605067）、双入口左心室（DILV）、肺动脉闭锁（OMIM# 265150）和左心发育不良综合征（OMIM# 241550，614435）。单心室心脏存在串联回路，使得体静脉回流到右心室和肺动脉，结合从肺静脉回流到左心室并流出到身体的血流，与存活不相容。目前，对单心室冠心病的分子机制和细胞病因学的认识还很有限。碱性螺旋-环-螺旋因子Hand 2在第二心脏区域（SHF）的心肌、心外膜、心脏神经嵴细胞和内膜中表达。Hand 2缺失导致E10.5胚胎死亡，这是由于SHF衍生的心脏结构的生长减少。SHF祖细胞中Hand 2的Mef 2c-Cre缺失导致TA/ DILV表型。我们最近已经确定，观察到的单心室表型是一个直接后果的手2功能的endoterm。Hand 2在内分泌系统中的功能尚未研究。我们的研究结果导致了一个新的假设，即来自发育中的内皮细胞的信号传导在确定室间隔的位置方面至关重要，这可能潜在地解释了一些单心室CHD的病因。我们概述了一个策略，既表征手2 endoadhesion功能，以确定直接上游endoadhesion信号网络的手2，和发展endoadhesion内的手2下游转录目标。定义这些endofluorescence信号通路和发展程序的手2调节将阐明单心室表型的细胞病因和控制心室间隔的分子程序，从而扩大心室壁小梁形成和间隔形态发生的理解。