Gene Regulatory Networks for Cardiac Morphogenesis

心脏形态发生的基因调控网络

• 批准号: 9332973
• 负责人: Frank Leo Conlon
• 金额: $ 66.24万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9332973
• 关键词: Address; Biochemical; Birth; Cardiac; Clinical; Congenital Abnormality; Development; Endoderm; Erinaceidae; Etiology; Event; GLI gene; Gene Expression; Genomics; Goals; Growth; Heart; Heart Abnormalities; Heart Septum; Human; Infant; Laboratories; Life; Lung; Molecular; Morbidity - disease rate; Morphogenesis; Mus; Natural History; Operative Surgical Procedures; Pathway interactions; Patients; Proteins; Reagent; Regulation; Regulator Genes; Regulatory Element; Role; Signal Transduction; TBX5 protein; Tissues; Transcription Coactivator; Transcriptional Activation; Work; atrioventricular septal defect; base; combinatorial; congenital heart disorder; improved; in vivo; lung development; mortality; novel; progenitor; programs; smoothened signaling pathway; structural heart disease; transcription factor

Abstract Congenital Heart Disease (CHD), malformations of the heart present at birth, is the most common class of life-threatening birth defect. Atrioventricular Septal Defects (AVSDs) are a common and serious form of CHD in humans, comprising 5-10% of all CHD and a greater proportion of cases requiring surgical intervention. Gaining a mechanistic understanding of atrioventricular (AV) septation is an essential goal for improving clinical approaches to structural heart disease. This R01 is based on a paradigm shift in the understanding of AV septation. Whereas the canonical view of AV septation was based on intracardiac events centered at the endocardial cushion, recent work demonstrated that the T-box transcription factor Tbx5 is required in the Second Heart Field, outside of the heart proper, for AV septation. In this proposal, we harness this new understanding of AV septation to address the molecular and biochemical mechanisms underlying AV septation, using Tbx5 as an entry point. We propose to (1) define the molecular basis of TBX5 regulation of Wnt2, required for lung development and thereby AV septation, (2) identify the proteins that interact with and function with Tbx5 in the SHF for AV septation; and (3) define the biochemical mechanisms underlying the function of Tbx5 in the SHF. The ultimate aim of the proposed work is to understand the molecular and biochemical basis of AV septation. This proposal will increase understanding of the molecular ontogeny of human AVSDs. This work is an essential step towards defining the causes of human CHD and improving the natural history of patients with CHD.

抽象的 先天性心脏病 (CHD) 是出生时出现的心脏畸形，是最常见的疾病 常见的一类危及生命的出生缺陷。房室间隔缺损 (AVSD) 是一种 人类常见且严重的 CHD，占所有 CHD 的 5-10%， 需要手术干预的病例比例。获得机械性的理解 房室（AV）间隔是改善结构性临床方法的一个基本目标 心脏病。 R01 基于对 AV 间隔理解的范式转变。鉴于 房室间隔的经典观点基于以心内膜为中心的心内事件 垫，最近的工作表明 T 盒转录因子 Tbx5 在 第二心区，位于心脏本身之外，用于 AV 分隔。在这个提案中，我们利用 对房室间隔的新认识解决了分子和生化机制 潜在的 AV 分隔，使用 Tbx5 作为入口点。我们建议（1）定义分子 TBX5 调节 Wnt2 的基础，是肺发育和 AV 间隔所需的，(2) 识别 SHF 中与 Tbx5 相互作用并发挥作用的蛋白质，以实现 AV 分隔；和 (3) 定义SHF中Tbx5功能的生化机制。 拟议工作的最终目的是了解分子和生化基础 房室间隔。该提议将增加对人类分子个体发育的理解 AVSD。这项工作是确定人类冠心病病因的重要一步 改善冠心病患者的自然史。