Endocardial mechanisms of cardiac trabeculation and septation

描述（申请人提供）：先天性心脏病（CHD）是最常见的出生缺陷。在各种冠心病中，由心室形态发生改变引起的单心室表型具有最差的临床预后，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）。单心室心脏呈串联回路，全身静脉回流到右心室和肺动脉，再加上从肺静脉回流到左心室并流出到身体的血流，这与生存是不相容的。目前，人们对多种形式的单心室冠心病的分子机制和细胞病因了解甚少。基本螺旋-环-螺旋因子Hand2在第二心野（SHF）心肌、心外膜、心神经嵴细胞和心内膜中表达。Hand2缺失导致E10.5胚胎致死，因为shf衍生的心脏结构生长减少。SHF祖细胞中Mef2c-Cre的缺失导致TA/ DILV表型。我们最近确定观察到的单心室表型是Hand2在心内膜功能的直接结果。Hand2在心内膜内的功能尚未被研究。我们的研究结果提出了一种新的假设，即来自心内膜发育的信号对于确定室间隔的位置至关重要，这可能解释了一些单心室冠心病的病因。我们概述了一种策略来描述Hand2的心内膜功能，确定Hand2的直接上游心内膜信号网络，以及Hand2在发育中的心内膜中的下游转录靶点。确定这些心内膜信号通路和Hand2调控的发育程序，将有助于阐明单心室表型的细胞病因学和控制室间隔的分子程序，从而扩大对心室壁小梁和室间隔形态发生的理解。

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.