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:
- 金额:$ 25.99万
- 依托单位:
- 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:
- 关键词:
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 Building on the published and our unpublished findings, we propose to pursue a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受影响患者
流出道 (OFT) 异常表明 OFT 形成特别容易出错。许多
受影响的患者活不过一岁生日。尽管最近在这方面取得了重大进展
了解 OFT 形成的分子基础,这是有关胚胎的核心问题
OFT 的起源仍有待确定。例如,目前尚不清楚心包内动脉是否
干,即主动脉干和肺干,起源于共同或不同的祖细胞池。
这个问题的答案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。流行的
人们相信主动脉干和肺干是圆锥干的衍生物——一种短暂的胚胎
结构,并来自共同的祖细胞库。然而,我们自己和其他人的研究结果
否则建议。基于已发表和未发表的研究结果,我们建议寻求
通过测试动脉干是起源于新结构的假设,提出了新颖的概念
来自不同的祖细胞库;及时部署这些祖先,由六人精心策划
依赖性转录程序,是 OFT 发展和多基因先心病发病机制的核心。
我们设计了三个具体目标:1)检查主动脉干和肺干是否正常。
本质不同,并相辅相成; 2)检查OFT是否形成
取决于六家族转录因子协调的祖细胞的及时部署; 3)
检查六家族转录因子是否是染色体 22q11.2 的遗传修饰剂
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,具有广泛的 OFT 缺陷,从中断的主动脉弓到
法洛四联症至总动脉干。 22q11.2DS 患者通常需要复杂的治疗
此后进行重建手术和终身专业护理。顺利完成拟议的
研究预计将挑战当前的教条,即动脉干是动脉干的衍生物
预先存在的结构,而且提供了一个新的概念框架来理解心脏 OFT
CHD 的发展和发病机制。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Sex as a predictor of response to cancer immunotherapy.
性别作为癌症免疫治疗反应的预测因子。
- DOI:10.1016/s1470-2045(18)30517-5
- 发表时间:2018
- 期刊:
- 影响因子:0
- 作者:Claggett,Brian;Tian,Lu;McCaw,ZacharyR;Takeuchi,Masahiro;Wei,Lee-Jen
- 通讯作者:Wei,Lee-Jen
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