Gene Regulatory Networks for Cardiac Morphogenesis

心脏形态发生的基因调控网络

• 批准号: 9889169
• 负责人: Frank Leo Conlon
• 金额: $ 61.95万
• 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/9889169
• 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.

摘要 先天性心脏病(CHD)是出生时就存在的心脏畸形，是 常见的危及生命的出生缺陷。房室间隔缺陷症是一种 人类常见和严重的冠心病，占所有冠心病的5%-10%，更大 需要手术干预的病例比例。获得对…的机械性理解 房室间隔是改进临床治疗房室间隔的基本目标。 心脏病。 这本R01是基于对房室间隔理解的范式转变。鉴于 房室间隔的标准观点是以心内膜为中心的心内事件 缓冲，最近的研究表明，T-box转录因子Tbx5在 心脏外的第二心区，用于房室间隔。在这项提案中，我们利用 这种对房室间隔的新认识解决了分子和生化机制 下层房室间隔，以Tbx5为切入点。我们建议(1)定义分子 Tbx5调节Wnt2的基础，是肺发育和房室间隔所必需的，(2) 确定与房室间隔的SHF中的Tbx5相互作用和起作用的蛋白质；以及 (3)明确Tbx5在SHF中作用的生化机制。 这项拟议工作的最终目的是了解 房室间隔。这一建议将增加对人类分子个体发育的理解 AVSD。这项工作是朝着确定人类CHD和 改善冠心病患者的自然病史。