TRANSCRIPTIONAL REGULATION OF CARDIOMYOCYTE DEVELOPMENT

描述（申请人的逐字描述）： 心血管系统是由一组复杂的分子途径调节的 将环境和发展信号转化为 心血管基因表达这些信号通路的扰动 与许多流行的人类心血管疾病有关 包括先天性心脏畸形、病理性心脏肥大，以及 扩张型心肌病在过去的十年里，我们研究了核武器。 转录因子调节的发展和功能， 哺乳动物心血管系统在最初的一系列实验中， 在5'端鉴定了心脏特异性转录启动子/增强子， 心肌肌钙蛋白C（cTnC）基因的侧翼区。我们用这个启动子 确定一组核转录因子， 在调节早期心肌细胞发育和心脏形态发生中的作用。 其中包括GATA 4锌指蛋白，它结合并反式激活 多种心脏特异性转录调控元件。使用 基因打靶方法，我们表明，GATA 4是必要的形成 在早期小鼠胚胎发育过程中的原始腹侧心管。更 最近，我们发现了第二种锌指蛋白，称为心脏的朋友， 加塔（CFOG）在发育中的心脏中表达， 特别是GATA 4的N-末端锌指。同样，奥尔森和 他的同事最近证明，GATA 4也与rel相关的 蛋白NFAT 3，这两种蛋白似乎是重要的调节剂， 心肌细胞肥大中所述研究的长期目标 这个持续的RO 1建议是为了了解分子机制， 加塔蛋白，与其他转录因子和共激活因子/ 阻遏蛋白调节心脏发生和心脏肥大。具体 我们将（1）绘制GATA 4发挥核心作用所需的区域， 心管的形成(2)从基因和生物化学上描述了 GATA 4和CFOG之间的相互作用，并了解这种作用的影响 （3）利用基因打靶技术， 确定NFAT 3和CFOG在心脏发育和功能中的作用， 鼠标总之，这些研究的结果应该提供新的基础， 对调节正常心脏发育的分子途径的见解 和功能它们也应该与理解分子 一些临床上重要的遗传性和获得性疾病的病理生理学 心血管疾病

DESCRIPTION (the applicant's description verbatim): The normal development of the cardiovascular system is regulated by a complex set of molecular pathways that interpret environmental and developmental signals into changes in cardiovascular gene expression. Perturbations of these signaling pathways have been implicated in a number of prevalent human cardiovascular diseases including congenital cardiac malformations, pathologic cardiac hypertrophy, and dilated cardiomyopathy. During the last ten years we have studied the nuclear transcription factors that regulate the development and function of the mammalian cardiovascular system. In an initial series of experiments we identified a cardiac-specific transcriptional promoter/enhancer in the 5' flanking region of the cardiac troponin C (cTnC) gene. We used this promoter to identify a set of nuclear transcription factors that appear to play important roles in regulating early cardiomyocyte development and cardiac morphogenesis. Among these was the GATA4 zinc finger protein that binds to and trans-activates a wide variety of cardiac specific transcriptional regulatory elements. Using a gene targeting approach we showed that GATA4 is necessary for the formation of the primitive ventral heart tube during early murine embryogenesis. More recently, we identified a second zinc finger protein called cardiac friend of GATA (CFOG) that is expressed in the developing heart and that binds specifically to the N-terminal zinc finger of GATA4. Similarly, Olson and coworkers recently demonstrated that GATA4 also interacts with the rel-related protein NFAT3 and that these two proteins appear to be important regulators of cardiac myocyte hypertrophy. The long term goal of the studies described in this continuing RO1 proposal is to understand the molecular mechanisms by which GATA proteins, in conjunction with other transcriptionfactors and coactivator/ repressor proteins regulate cardiogenesis and cardiac hypertrophy. Specifically we will (1) map the regions of GATA4 that are required for its central role in the heart tube formation. (2) genetically and biochemically characterize the interaction between GATA4 and CFOG and understand the effects of this interaction on the transcriptional activity of GATA4, (3) Use gene targeting to determine the roles of NFAT3 and CFOG in cardiac development and function in the mouse. Together, the results of these studies should provide novel basic insights into the molecular pathways that regulate normal cardiac development and function. They should also be relevant to understanding the molecular pathophysiology of a number of clinically important inherited and acquired cardiovascular diseases.