TRANSCRIPTIONAL REGULATION OF CARDIOMYOCYTE DEVELOPMENT

描述(申请人逐字描述)：正常发展 心血管系统受到一系列复杂的分子通路的调节。 将环境和发展信号解释为 心血管基因表达。这些信号通路的扰动有 与许多流行的人类心血管疾病有关 包括先天性心脏畸形，病理性心肌肥大，以及 扩张型心肌病。在过去的十年里，我们一直在研究核子 调节细胞发育和功能的转录因子 哺乳动物的心血管系统。在最初的一系列实验中，我们 在5‘端发现心脏特异的转录启动子/增强子 心肌肌钙蛋白C(CTNC)基因侧翼区。我们利用这个推动者 确定一组似乎发挥重要作用的核转录因子 在调控早期心肌细胞发育和心脏形态发生中的作用。 其中包括与GATA4锌指蛋白结合并反式激活的蛋白 各种各样的心脏特异转录调控元件。使用 基因打靶的方法表明GATA4在肿瘤的形成中是必需的。 小鼠胚胎发育早期的原始腹心管。更多 最近，我们鉴定了第二个锌指蛋白，名为心脏之友 GATA(CFOG)，它在发育中的心脏中表达，并与 具体到GATA4的N-末端锌指。同样，奥尔森和 同事们最近证明，GATA4也与REL相关的 蛋白质NFAT3和这两种蛋白质似乎是重要的调节因子 心肌细胞肥大。中描述的研究的长期目标 这一持续的RO1提议是为了了解 GATA蛋白与其他转录因子和辅活化子/ 抑制蛋白调节心脏发生和心肌肥厚。特指 我们将(1)绘制GATA4的区域图，这些区域是其在 心脏导管的形成。(2)从遗传学和生物化学的角度描述 GATA4与CFOG的互动及其影响 相互作用对GATA4转录活性的影响，(3)利用基因打靶技术 确定NFAT3和CFOG在心脏发育和功能中的作用 那只老鼠。总而言之，这些研究的结果应该会提供新的基础 对调节正常心脏发育的分子途径的洞察 和功能。它们也应该与理解分子有关 一些临床上重要的遗传性和获得性遗传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.