TRANSCRIPTIONAL REGULATORS OF CARDIAC GENE EXPRESSION

描述（改编自研究者摘要）：先天性

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.