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），出生时出现心脏的畸形，是最大的 危及生命的出生缺陷的常见类别。心室间隔缺陷（AVSD）是一个 人类中常见和严重的冠心病形式，占全冠心的5-10％，更大 需要手术干预的病例比例。对机械理解 心室（AV）分隔是改善结构性临床方法的基本目标 心脏病。 该R01基于对AV分隔的理解的范式转变。而 AV分隔的规范视图是基于心室内的心脏内事件 垫子，最近的工作表明，在 第二个心脏场，适当的心脏，用于AV分隔。在此提案中，我们利用 对AV分隔的新理解，以解决分子和生化机制 基础AV分隔，使用TBX5作为入口点。我们建议（1）定义分子 Wnt2的TBX5调节基础，肺发育所需，从而进行AV分隔，（2） 确定与SHF中与TBX5相互作用并功能的蛋白质以进行AV分隔；和 （3）定义SHF中TBX5功能的基础的生化机制。 拟议工作的最终目的是了解分子和生化基础 AV分隔。该建议将增加对人分子个体发育的理解 AVSD。这项工作是定义人类冠心病的原因的重要一步 改善冠心病患者的自然史。