Grant: Discovery Grants Program - Individual

One of the major mechanisms thought to facilitate the increasing complexity of organisms in the evolution of life is duplication of genes and entire genomes. We are investigating the regulation and evolution of duplicated genes belonging to the multigene family coding for intracellular lipid-binding proteins (iLBP) of zebrafish. This family includes the fatty acid-, retinol- (a vitamin A derivative) and retinoic acid-binding proteins of zebrafish. iLBPs have been implicated in a myriad of cellular processes from uptake and intracellular transport of long-chain fatty acids, bile salts and retinoids, to modulating gene regulation, neurogenesis, and disease states in humans. We chose zebrafish as the experimental model organism for our studies as it is hardy, disease resistant, easily and inexpensively reared, and useful in the application of both experimental embryology and genetic analysis. Moreover, zebrafish is a model system to study vertebrate development in which stages of embryogenesis are well characterized. To date, we have characterized 22 members of the zebrafish iLBP multigene family. Many iLBP genes are duplicated owing to a whole genome duplication event that occurred in the ray-finned fish lineage ~230-400 million years ago. We have shown that transcription of several zebrafish iLBP genes is induced by dietary fatty acids and we propose to test whether duplicated copies of these iLBP genes have been retained in the zebrafish genome owing to evolution of function(s). The objectives of the proposed studies are to identity the cis-acting elements in the iLBP gene-promoters. Furthermore, we plan to determine which nuclear transcription factors and their activating ligands (e.g., fatty acids and clofibrate, a drug known to induce some mammalian genes involved in lipid metabolism) bind cis-elements to induce specific iLBP genes, and how these cis- and trans-acting factors evolved. In addition, since many of the genes that control normal embryogenesis, growth and reproduction in zebrafish are similar, or the same, in mammals, our studies using zebrafish as a model system may provide insights into the roles of the iLBP genes implicated in human development and disease, such as diabetes, atherosclerosis and obesity.