A major goal of moderm biology is to determine how cells organize into three-dimensional structures that give rise to organs. Organogenesis that involves the development of complex tubular structures such as the lung, kidney, and vascular tree present an especially challenging problem. The cellular interactions, genetic programs and signal transduction pathways that give rise to these structures during development may become disrupted during pathological situations such as cancer or vascular injury. Recently, branching morphogenesis of the Drosophila tracheal system has been shown to be regulated by a Drosophila homolog of the fibroblast growth factor (FGF) family called Branchless and its receptor Breathless, a receptor tyrosine kinase. In the Drosophila tracheal system, new branches sprout from the growing ends of these tracheal buds. An antagonist of FGF signaling called Sprouty (Spry) regulates this apical bias. In flies mutant for the Spry gene, excessive branching occurs. Three human Spry homologs have been identified in the expressed sequence tag database (dbEST) and have been designated hSpry 1, hSpry2 and hSpry3. hSpry2 encodes a 315-residue polypeptide that contains a cysteine-rich domain with 51 percent identity to Drosophila Spry. Data from this laboratory indicates that hSpry2 is expressed in human umbilical vein endothelial cells and that its expression is up regulated by stimulation with FGF or tumor-promoting phorbol esters. These results are consistent with data from Drosophila indicating that Branchless (FGF) induces Spry expression thus creating a feedback mechanism for control of FGF signaling. Since FGF is angiogenic in vivo, we hypothesize that Spry2 may play a role in branching morphogenesis of the vascular system and that the regulatory pathway between FGF and Spry may be disrupted during tumor angiogenesis or other pathological situations involving unregulated vessel formation. To address this hypothesis we propose the following specific aims: 1) To determine the function and site(s) of action of Spry polypeptides on the FGF and VEGF signal transduction pathways using in vitro and in vivo approaches; and 2) To determine whether Spry regulates FGF or VEGF-induced endothelial cell growth, migration and/or differentiation using in vitro and in vivo models. These studies are likely to provide novel insight into the role of Spry in regulating endothelial cell function and may suggest strategies for therapeutic intervention of vascular disease.
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