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）是最常见的先天缺陷。在各种CHD中，心室形态发生变化引起的单个心室表型的临床预后最差，包括三尖闭锁（TA; OMIM＃605067），双入口左心室（DILV），肺动脉症（OMIM＃265150）和左心脏造成心脏效开论（OMIM＃265150），以及左心脏综合征（OMIM＃265150）（emim＃265150）。单个心脏心脏上有一个串联电路，使系统的静脉恢复到右心室和肺动脉，并结合了肺静脉恢复到左心室的流动，并向外返回身体，与生存不相容。当前，对多种形式的单个心室冠心病的分子机制和细胞病因的理解不足。基本的螺旋 - 环螺旋因子手2在第二心脏场（SHF），心外膜，心脏神经rest细胞和心内膜心肌的心肌内表达。 Hand2缺失导致E10.5胚胎致死性，这是由于SHF衍生的心脏结构的生长降低。 SHF祖细胞的MEF2C-CRE删除了Hand2，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手2功能的直接结果。尚未研究Hand2在心内膜内的功能。我们的发现导致了一个新的假设，即发育中的心内膜信号对于确定心室隔膜的位置至关重要，这可能可以解释某些单个心室CHD的病因。我们概述了既表征Hand2心内膜功能的策略，以确定Hand2的直接上游心内膜信号网络，也可以识别发育中的心内膜心脏中的Hand2-Downstream转录目标。定义由Hand2调节的这些心内膜信号通路和发育程序将阐明单个心室表型的细胞病因以及控制心室分离的分子程序，从而扩展了对心室壁小径的理解，以及隔膜形态发生。