MOLECULAR BASIS FOR HYPOPLASTIC HEART SYNDROMES

心脏发育不全综合征的分子基础

• 批准号: 6490612
• 负责人: ERIC N Olson
• 金额: $ 114.5万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6490612
• 关键词: congenital cardiovascular disorder; developmental genetics; embryogenesis; gene expression; neural crest

Congenital heart defects account for the largest number of birth defects in humans. Many heart defects can be attributed to abnormalities in specific steps in cardiac development, particularly in the formation and function of the ventricular chambers and in the neural crest-derived components of the heart. While the embryologic events involved in heart development have been carefully documented, little is known of the underlying mechanisms and molecules that control cardiac myogenesis and morphogenesis. The overall goal of this project is to elucidate the molecular mechanisms involved in specification and development of the ventricular chambers and the cardiac neural crest and to identify the genes responsible for defects in these cardiac compartments in three human chambers and the cardiac neural crest and to identify the genes responsible for defects in these cardiac compartments in three human syndromes associated with congenital heart disease: hypoplastic left heart syndrome, Down syndrome, and DiGeorge syndrome. Recently, the Olson lab found that two novel bHLH transcription factors, referred to as dHAND and eHAND, are expressed in specific subsets of ventricular precursor cells and in the cardiac neural crest and that mouse mutants lacking dHAND fail to form a right ventricle specification and cardiac neural crest and that mouse mutants lacking dHAND fail to form a right ventricle or cardiac neural crest derivatives. The discovery of these molecules provides a molecular entry point into the mechanisms for ventricular specification and cardiac neural crest development and establishes a conceptual framework for the overall SCOR. The SCOR contains four interwoven projects and three cores that encompass basic molecular strategies to understand cardiac development and clinical studies to identify the gens responsible for congenital heart diseases in which the ventricular and neural crest components of the heart are affected. The projects are as follows. 1) E. Olson will define the roles of the HAND family of cardiac basic helix-loop-helix (bHLH) transcription factors in normal and abnormal cardiac development. 2) D. Srivastava will define the downstream target genes regulated by dHAND in the developing heart, with particular attention to a recently discovered gene that is dHAND-dependent and is localized to the minimal chromosomal deletion in DiGeorge syndrome. 3) K. Chien will clone and characterize the gene responsible for hypoplastic left heart syndrome. 4) Korenberg will identify the gene(s) responsible for heart defects in Down syndrome. The possibility that one of the candidate genes, which encodes a novel cell adhesion molecule, called DS-CAM, is a transcriptional target for MEF2 will also be addressed. Each of these projects is interrelated through the creation of novel strains of mouse mutants in which key cardiogenic regulatory genes can be inactivated in a temporal- and compartment-specific manner within the developing heart. These studies will provide an in-depth understanding of the basic molecular pathways that regulate heart development and the ways in which these pathways can be disrupted in congenital heart diseases.

先天性心脏病是人类出生缺陷中数量最多的。 许多心脏缺陷可归因于心脏发育特定步骤的异常，特别是心室的形成和功能以及心脏的神经嵴衍生成分的异常。 虽然心脏发育中涉及的胚胎学事件已被仔细记录，但人们对控制心肌发生和形态发生的潜在机制和分子知之甚少。 该项目的总体目标是阐明心室腔室和心脏神经嵴的规范和发育所涉及的分子机制，并确定导致三个人体心室和心脏神经嵴中这些心脏室缺陷的基因，并确定与先天性心脏病相关的三种人类综合症中这些心脏室缺陷的基因：左心发育不全综合症、唐氏综合症和迪乔治综合症。 最近，Olson 实验室发现两种新型 bHLH 转录因子（称为 dHAND 和 eHAND）在心室前体细胞的特定亚群和心脏神经嵴中表达，并且缺乏 dHAND 的小鼠突变体无法形成右心室规范和心脏功能。神经嵴和缺乏 dHAND 的小鼠突变体无法形成右心室或心脏神经嵴衍生物。 这些分子的发现为心室规范和心脏神经嵴发育机制提供了一个分子切入点，并为整体 SCOR 建立了概念框架。 SCOR 包含四个相互交织的项目和三个核心，其中包括了解心脏发育的基本分子策略和临床研究，以确定导致先天性心脏病（心脏的心室和神经嵴成分受到影响）的基因。 项目如下。 1) E. Olson 将定义心脏碱性螺旋-环-螺旋 (bHLH) 转录因子 HAND 家族在正常和异常心脏发育中的作用。 2) D. Srivastava 将定义发育中心脏中 dHAND 调节的下游靶基因，特别关注最近发现的 dHAND 依赖性基因，并且位于 DiGeorge 综合征中的最小染色体缺失。 3) K. Chien 将克隆并鉴定导致左心发育不良综合征的基因。 4) Korenberg 将鉴定导致唐氏综合症心脏缺陷的基因。 编码一种新型细胞粘附分子 DS-CAM 的候选基因之一可能是 MEF2 的转录靶标，这一可能性也将得到解决。 这些项目中的每一个都通过创建新的小鼠突变体品系而相互关联，其中关键的心源性调节基因可以在发育中的心脏内以时间和区室特异性的方式失活。这些研究将深入了解调节心脏发育的基本分子途径以及先天性心脏病中这些途径被破坏的方式。