TRANSCRIPTIONAL REGULATORS OF CARDIAC GENE EXPRESSION

描述（改编自研究者摘要）：先天性 心脏畸形，发生频率约为10/ 1，000名活产婴儿，是心脏病的主要原因之一， 孩子 死胎中这种畸形的发生率可能是 大十倍。 对这些分子基础的理解 异常需要控制心脏的基因信息 形态发生和心脏基因表达。 几个关键成员的 心源性调节网络在果蝇和脊椎动物中是保守的。 关于转录调节因子，果蝇的利用 遗传学允许在功能分析上的快速进展， tinman和D-mef 2基因以及类似的基因研究正在进行中， 鼠标系统 在本研究中， Tinman蛋白功能和D-mef 2心脏表达的追求，试图 以确定果蝇心脏发生的其他调节因子。 初步数据表明，Tinman需要一种共激活蛋白， D-mef 2在心脏中的直接表达，另一个因素必须是 D-mef 2在完整补体中的功能所需的。 还有， 最近的研究表明，果蝇心脏的所有线粒体细胞 在基因上并不相同，这一发现与 不同群体之间转录调控的差异 心肌细胞在脊椎动物心脏发育中的作用。 总体看 这些额外的心源性因素的特征，以及遗传 对不同亚型间充质干细胞特化的剖析 人口，应该提供重要的见解，基本机制 控制果蝇的心脏发育和心脏基因表达， 高等真核生物包括人类。

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.