The Six-Family Genes in Cardiovascular Development And Disease

先天性心脏病是导致出生缺陷的头号原因。近1/3的受影响患者 具有流出道（OFT）异常，表明OFT形成特别容易出错。许多 受影响的病人活不过一岁生日尽管最近取得了重大进展， 了解OFT形成的分子基础，关于胚胎发育的核心问题， 公平贸易的起源仍有待确定。例如，目前尚不清楚心包内动脉是否 树干，即，主动脉和肺动脉干起源于共同或不同的祖细胞库。 这个问题的答案是至关重要的，以了解形态发生过程中分离的系统性 和肺循环以及导致OFT异常的病理过程。流行的 有一种观点认为，主动脉和肺动脉干是圆锥动脉干的衍生物，圆锥动脉干是一种短暂的胚胎干， 结构，以及来自祖细胞的共同池。然而，我们自己和其他人的研究结果表明， 不是这么说的基于已发表和未发表的研究结果，我们建议开展一项 通过检验动脉干是起源于血管的新生结构的假设， 从不同的祖细胞池;及时部署这些祖细胞，由一个六- 依赖于转录程序，是多基因CHD的OFT发展和发病机制的核心。 我们设计了三个具体目标：1）检查主动脉和肺动脉干是否 本质上是不同的，并协调地添加到心脏; 2）检查是否OFT形成 依赖于由六家族转录因子协调的祖细胞的及时部署; 3） 研究Six家族转录因子是否是染色体22q11.2的遗传修饰因子 缺失综合征（22q11.2DS）或DiGeorge综合征。22q11.2DS是最常见的染色体 微缺失综合征伴有广泛的OFT缺陷，从主动脉弓中断到 法洛四联症至总动脉干。22q11.2DS患者通常需要复杂的 重建手术和终身专业护理。圆满完成拟议的 这项研究有望挑战目前的教条，即动脉干是动脉的衍生物。 此外，还提供了一个新的概念框架来理解心脏OFT 冠心病的发生、发展及发病机制。

Congenital heart disease is the number one cause of birth defects. Nearly 1/3 of the affected patients have outflow tract (OFT) anomalies indicating that OFT formation is particularly prone to error. Many of the affected patients won't live past their first year birthday. Despite the significant recent advances in understanding the molecular basis of OFT formation, the central question regarding the embryonic origins of OFT remains to be defined. For example, it is still unclear whether the intrapericardial arterial trunks, i.e., the aortic and pulmonary trunks, originate from the common or different pools of progenitors. Answer to the question is critical to understanding the morphogenetic process separating the systemic and pulmonary circulations and, the pathological process leading to the OFT anomalies. The popular belief is that the aortic and pulmonary trunks are derivatives of conotruncus - a transient embryonic structure, and from the common pool of progenitors. However, results from our own studies and others suggest otherwise. Building on the published and our unpublished findings, we propose to pursue a novel concept by testing the hypothesis that the arterial trunks are de novo structures that originate from different pools of progenitors; timely deployment of these progenitors, orchestrated by a Six- dependent transcriptional program, is central to OFT development and pathogenesis of polygenic CHDs. We have designed three specific aims: 1) to examine whether the aortic and pulmonary trunks are intrinsically different, and are coordinately added to the heart; 2) to examine whether OFT formation depends on the timely deployment of progenitors orchestrated by the Six-family transcription factors; 3) to examine whether Six-family transcription factors are genetic modifiers of chromosome 22q11.2 deletion syndrome (22q11.2DS) or DiGeorge syndrome. 22q11.2DS is the most common chromosome microdeletion syndrome with a wide spectrum of OFT defects ranging from the interruptive aortic arch to tetralogy of Fallot to common arterial trunk. Patients with 22q11.2DS often require complex reconstructive surgeries and lifelong specialized cares thereafter. Successful completion of the proposed research is expected to challenge the current dogma that the arterial trunks are derivatives of the preexisting structure and, moreover, provide a new conceptual framework to understand cardiac OFT development and pathogenesis of CHD.