THE ROLE OF SRF IN CARDIAC FUNCTION AND DEVELOPMENT

SRF 在心脏功能和发育中的作用

• 批准号: 6740796
• 负责人: RAVINDRA P MISRA
• 金额: $ 37.5万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6740796
• 关键词: congenital heart disorder; developmental genetics; early embryonic stage; embryonic stem cell; genetically modified animals; heart function; histogenesis; laboratory mouse; mammalian embryology; transcription factor

The overall objective of this application is to elucidate underlying molecular mechanisms involved in cardiac function and heart formation. Congenital cardiovascular anomalies are the most common form of human birth defect with a recorded instance of 1 per 200 liver births per year in North America. There is therefore considerable interest in understanding the molecular and genetic bases of these diseases. Recent evidence in rodent systems indicates that the serum response factor (SRF), a member of the MADS (MCMI, Agamous and Deficiens, SRF) box family of transcription factors, is a critical regulator of cardiac development and function. SRF has been shown to regulate various cardiac and skeletal muscle specific genes necessary for normal cardiac development and function, including the cardiac and skeletal actin, dystrophin, myosin light chain and atrial natriuretic peptide genes. Consistent with this, cardiac specific over-expression of SRF in transgenic animals results in reinduction of an embryonic program of gene expression that can lead to dramatic cardiac hypertrophic and myopthic phenotypes that mimic those observed during the initial development of congestive heart failure in humans. However, knock-out of the SRF gene is embryonic lethal prior to cardiac differentiation. Therefore, despite a central place for SRF in heart function and development the role of SRF in heart formation in vivo has not been carefully investigated. In the current application we propose to study the role of SRF during early cardiogenesis using a powerful novel transgenic approach in which targeted gene insertion of dominant inhibitory versions of SRF is coupled with embryonic stem cell aggregation techniques. The results changes in SRF target gene expression and cardiac morphology of early stage embryos will then be analyzed. These studies will both elucidate the mechanisms by which SRF functions in heart and will establish powerful new methodologies for studying heart formation and function.

该应用的总体目标是阐明涉及心脏功能和心脏形成的潜在分子机制。先天性心血管异常是最常见的人类出生缺陷，据记录，北美每年每 200 名肝脏新生儿中就有 1 人患有先天性心血管异常。因此，人们对了解这些疾病的分子和遗传基础非常感兴趣。啮齿动物系统的最新证据表明，血清反应因子 (SRF) 是转录因子 MADS（MCMI、Agamous 和 Deficiens，SRF）盒家族的成员，是心脏发育和功能的关键调节因子。 SRF 已被证明可以调节正常心脏发育和功能所需的各种心脏和骨骼肌特异性基因，包括心脏和骨骼肌肌动蛋白、肌营养不良蛋白、肌球蛋白轻链和心房钠尿肽基因。与此相一致的是，转基因动物中SRF的心脏特异性过度表达导致胚胎基因表达程序的重新诱导，从而导致显着的心脏肥厚和肌视表型，类似于人类充血性心力衰竭最初发展过程中观察到的表型。然而，SRF 基因的敲除在心脏分化之前是胚胎致死的。因此，尽管 SRF 在心脏功能和发育中处于中心地位，但 SRF 在体内心脏形成中的作用尚未得到仔细研究。在当前的应用中，我们建议使用一种强大的新型转基因方法来研究SRF在早期心脏发生过程中的作用，其中显性抑制版本的SRF的靶向基因插入与胚胎干细胞聚集技术相结合。然后将分析早期胚胎的 SRF 靶基因表达和心脏形态的结果变化。这些研究将阐明 SRF 在心脏中发挥作用的机制，并将建立研究心脏形成和功能的强大新方法。