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。近三分之一的受影响患者 有流出道(OFT)异常，表明流出道地层特别容易出错。许多. 受影响的患者活不过一岁生日。尽管最近在以下方面取得了重大进展 了解OFT形成的分子基础，这是关于胚胎的中心问题 OFT的起源仍有待界定。例如，目前仍不清楚心包内动脉是否 主干和肺干起源于共同的或不同的祖细胞池。 对这个问题的回答对于理解分离系统的形态发生过程至关重要 和肺循环以及导致OFT异常的病理过程。受欢迎的 人们认为，主动脉和肺动脉干是圆锥动脉干的衍生品--一种短暂的胚胎 结构，并从共同的祖先池中。然而，我们自己的研究和其他人的结果 但建议并非如此。根据已发表和未发表的研究结果，我们建议进行一项 通过检验动脉干是起源于新生结构的假说而提出的新概念 来自不同的祖先池；及时部署这些祖先，由六个- 依赖的转录程序，是OFT发生和多基因CHD发病机制的核心。 我们设计了三个具体的目标：1)检查主动脉和肺动脉干是否 本质上不同，并被协调地添加到心脏；2)检查OFT是否形成 依赖于六个家族转录因子编排的祖细胞的及时部署；3) 检测六个家族转录因子是否为染色体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 伴有广泛OFT缺陷的微缺失综合征，范围从主动脉弓中断到 法洛四联症至共同动脉干。22q11.2DS患者通常需要复杂的 重建手术和之后的终身专门护理。圆满完成拟议中的 预计研究将挑战目前的教条，即动脉干是 并为理解心脏OFT提供了一个新的概念框架 冠心病的发生发展和发病机制。

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 Building on the published and our unpublished findings, we propose to pursue a novel concept by testing the hypothesis that the arterial trunks are de novo structures that originate from different pools of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.