MEF2 Function in Cardiac Muscle Development

MEF2 在心肌发育中的功能

基本信息

批准号：
6898851
负责人：
Francisco J Naya
金额：
$ 32.3万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2007-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6898851
关键词：
biotechnology cardiac myocytes cardiogenesis congenital heart disorder developmental genetics embryogenesis functional /structural genomics gene expression gene targeting genetic regulation genetically modified animals laboratory mouse microarray technology myocardium myocardium disorder phenotype transcription factor

项目摘要

DESCRIPTION (provided by applicant): Formation of a functional, multi-chambered heart involves a complex regulatory network of signaling molecules and transcription factors. Perturbations at any step in this process often result in severe morphological and/or functional defects. Thus, understanding the function of cardiac developmental control genes will reveal important clues into the genetic basis of congenital heart malformations. A transcription factor that plays an important role in cardiac muscle development is the MEF2 protein family. Loss-of function mutations in rnef2 in flies and in mice disrupt the appropriate development of cardiac muscle. Hence, a comprehensive in vivo analysis of mef2 will lead to a better understanding of the genetics and molecular mechanisms of heart development. In vertebrates, MEF2 is encoded by four genes, mef2a,-b,-c, and -d that are coexpressed in muscle and non-muscle lineages and whose functions in vitro are largely interchangeable. However, targeted mutations in mice have revealed distinct roles for mef2a and mef2c in cardiac development, mef2a null mice exhibit a post-natal cardiomyopathy with severe cytoarchitectural and mitochondrial defects in the multi-chambered heart whereas mef2c mutant mice display altered cardiac looping morphogenesis during embryogenesis. Given the distinct cardiac phenotypes, the mechanisms by which closely related genes within a multigene family uniquely regulate cellular differentiation in vivo will be explored. Because the mef2a knockout mice represent a potential connection to human cardiac disease a thorough developmental and genetic analysis will be initiated. The proposed research will address these questions using gene targeting and transgenic approaches in mice. The specific aims are: 1) to generate a conditional knockout for the mef2a gene to determine the tissue-specific and temporal requirement for mef2a in cardiac muscle cells and the role of mef2a in the adult heart, 2) to create knock-in alleles for the mef2a and mef2c genes to examine possible functional redundancy between these two vertebrate mef2 genes, and 3) to dissect the molecular mechanisms of the post-natal cardiomyopathy in mef2a knockout mice by identifying and characterizing genes dysregulated in mutant hearts. The elucidation of MEF2-dependent transcriptional pathways in vivo will be an important step in the development of genetic strategies to treat cardiovascular disease.

描述（由申请人提供）：功能性多腔心脏的形成涉及信号分子和转录因子的复杂调节网络。该过程中任何步骤的扰动通常会导致严重的形态和/或功能缺陷。因此，了解心脏发育控制基因的功能将揭示先天性心脏畸形的遗传基础的重要线索。 MEF2 蛋白家族是在心肌发育中起重要作用的转录因子。果蝇和小鼠中 rnef2 的功能丧失突变会破坏心肌的正常发育。因此，对 mef2 进行全面的体内分析将有助于更好地了解心脏发育的遗传学和分子机制。在脊椎动物中，MEF2 由四个基因 mef2a、-b、-c 和 -d 编码，这些基因在肌肉和非肌肉谱系中共表达，并且其体外功能在很大程度上是可互换的。然而，小鼠的靶向突变揭示了mef2a和mef2c在心脏发育中的不同作用，mef2a缺失小鼠表现出产后心肌病，多腔心脏中存在严重的细胞结构和线粒体缺陷，而mef2c突变小鼠在胚胎发生过程中表现出改变的心脏循环形态发生。鉴于不同的心脏表型，将探索多基因家族中密切相关的基因独特地调节体内细胞分化的机制。由于 mef2a 敲除小鼠与人类心脏病存在潜在联系，因此将启动彻底的发育和遗传分析。拟议的研究将利用小鼠基因靶向和转基因方法来解决这些问题。具体目标是：1) 产生 mef2a 基因的条件敲除，以确定心肌细胞中 mef2a 的组织特异性和时间需求以及 mef2a 在成人心脏中的作用，2) 为 mef2a 基因创建敲入等位基因mef2a 和 mef2c 基因检查这两个脊椎动物 mef2 基因之间可能的功能冗余，以及 3) 剖析 mef2a 产后心肌病的分子机制通过识别和表征突变心脏中失调的基因来敲除小鼠。体内 MEF2 依赖性转录途径的阐明将是开发治疗心血管疾病的遗传策略的重要一步。