The Six-Family Genes in Cardiovascular Development And Disease

心血管发育和疾病的六家族基因

基本信息

批准号：
10360298
负责人：
Xue Sean Li
金额：
$ 25.99万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10360298
关键词：
Six Family Genes Cardiovascular Development

项目摘要

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 Building on the published and our unpublished findings, we propose to pursue a novel concept by testing the hypothesis that the arterial trunks are de novo structures that originate from different pools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

先天性心脏病是出生缺陷的第一大原因。近1/3的患者具有流出路（通常）异常，表明FEST形成特别容易出现错误。许多受影响的患者不会过着他们的第一年生日。尽管最近取得了重大进展了解OFT形成的分子基础，这是有关胚胎的核心问题 FEST的起源仍有待定义。例如，目前尚不清楚脑内动脉是否树干，即主动脉和肺部躯干，源自祖细胞的常见或不同池。回答问题对于理解分隔系统的形态发生过程至关重要和肺循环以及导致常规异常的病理过程。受欢迎的认为主动脉和肺部的树干是Conotruncus的衍生物 - 一种短暂的胚胎结构，以及祖细胞的共同库。但是，我们自己的研究和其他研究的结果建议这样做。在已发布和未发表的发现的基础上，我们建议追求通过测试动脉树干是从头结构的假设，通过测试新概念来自不同的祖细胞；及时部署这些祖先，由六个依赖的转录程序是多基因CHD的经常发育和发病机理的核心。我们设计了三个具体目标：1）检查主动脉和肺部的树干是否是本质上不同，并协调地添加到心脏中； 2）检查是否会形成取决于六户转录因子策划的祖细胞的及时部署； 3）检查六户转录因子是否是染色体22q11.2的遗传修饰剂删除综合征（22q11.2ds）或Digeorge综合征。 22q11.2ds是最常见的染色体微骨骼综合征，其范围很广的缺陷范围从中断主动脉弓到 Fallot的四部曲到普通的动脉躯干。 22q11.2d的患者通常需要复杂此后，重建手术和终身专业护理。成功完成拟议的预计研究将挑战当前的教条，即动脉躯干是此外，先前存在的结构，并提供了一个新的概念框架来了解心脏 CHD的发育和发病机理。