TRANSCRIPTIONAL REGULATORS OF CARDIAC GENE EXPRESSION

描述(改编自调查人员摘要)：先天性 心脏畸形，发生频率约为10% 1,000名活产婴儿是#年心脏病的主要原因之一 孩子们。这种畸形在死产中的频率可能是 差不多是原来的10倍。对这些的分子基础的理解 异常情况需要有关控制心脏的基因的信息。 形态发生和心脏基因表达。该委员会的几个关键成员 在果蝇和脊椎动物中，心源性调节网络是保守的。 关于转录调节因子，果蝇的利用 遗传学允许在细胞的功能分析方面取得快速进展 Tinman和D-MEF2基因以及类似的遗传学研究目前正在 鼠标系统。在这项研究方案中，对 Tinman蛋白功能和D-MEF2心脏表达的研究 以确定果蝇心脏生成的其他调节因子。 初步数据显示，Tinman需要一种辅助激活蛋白来 D-MEF2在心脏中的直接表达，还有一个因素必须是 D-MEF2在完整的心肌细胞中发挥作用所必需的。另外， 最近的研究表明，果蝇心脏的所有心肌细胞 在基因上并不相同，这一发现与 不同群体间转录调控的差异 心肌细胞在脊椎动物心脏发育中的作用。总体而言， 这些额外的心脏致病因子的特征，以及基因 对不同亚型心肌细胞规格的剖析 应该为基本机制提供重要的见解 控制果蝇心脏发育和心脏基因表达 包括人类在内的高等真核生物。

DESCRIPTION (adapted from investigator's abstract): Congenital malformations of the heart, which occur with a frequency of about 10 per 1,000 live births, are among the major causes of cardiac disease in children. The frequency of such malformations among stillbirths may be as much as 10-fold greater. An understanding of the molecular basis for these anomalies will require information on the genes that control heart morphogenesis and cardiac gene expression. Several key members of the cardiogenic regulatory network have been conserved in flies and vertebrates. Concerning transcriptional regulators, the utilization of Drosophila genetics has allowed for rapid progress on the functional analysis of the tinman and D-mef2 genes and similar genetic studies are now underway in the mouse system. In this research proposal, the further investigation of Tinman protein function and D-mef2 heart expression is pursued, attempting to identify additional regulators of cardiogenesis in Drosophila. Preliminary data indicate that Tinman requires a coactivator protein to direct D-mef2 expression in the heart and yet another factor must be required for D-mef2 function in the full complement of cardial cells. Also, recent work has demonstrated that all cardial cells of the Drosophila heart are not genetically identical, a finding that is comparable to the differences seen in transcriptional regulation between different populations of cardiomyocytes in vertebrate heart development. Overall, the characterization of these additional cardiogenic factors, and the genetic dissection of the specification of distinct subtypes of cardial cell populations, should provide important insights into fundamental mechanisms controlling heart development and cardiac gene expression in flies and higher eukaryotes including humans.