EXCEED THE SPACE PROVIDED. Growth factors induce a variety of cellular responses including proliferation, survival and migration. A number of growth factors activate receptors with intrinsic tyrosine kinase activity. Extensive studies in cell culture systems has shown that receptor engagement leads to binding of intracellular effectors, and the activation of individual signaling pathways. Prior studies from our laboratory have focused on identifying the roles of signaling pathways downstream of platelet derived growth factors (PDGFs), which are involved in developmental and physiological responses in many tissues, including the vasculature, the kidney, the skeleton and neural crest derivatives. For the continuation period, we propose to further study roles of PDGFRs together with Fibroblast Growth Factor Receptors (FGFRI) and cytoplasmic ephrins (ephrin-Bs) in neural crest and vascular development. Crosstalk with novel candidate signaling pathways will also be examined. The proposed studies will utilize phenotypic analysis, expression profiling and lineage mapping to help us further understand neural crest development, as well as communication between vascular smooth muscle cells and endothelial cells during the establishment of the circulatory system. Because mutations that activate the PDGF receptors have often been found to be associated with various cancers, we propose to make mutations in the mouse that will mimic these processes. We will use cells derived from mutants in which individual signals have been removed or where the receptor is activated to further analyze crosstalk with integrin receptors. These studies should help us understand growth factor regulatory mechanisms, and provide information on the specificity and interplay of growth factor signaling pathways in physiological processes. Ultimately, these studies should be beneficial for the treatment of congenital birth defects associated with abnormal neural crest or vascular development.
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