Tracheal Development in Drosophila: Angiogenic models

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DESCRIPTION (provided by applicant)The development of the trachea in Drosophila, a tubular network, is a model for angiogenesis, with numerous tracheal-regulating gene products having counterparts in mammalian angiogenesis. Regulation of vascular outgrowth has a critical role in the growth and maintenance of solid tumors, as well as in the progress of non-solid tumor malignancies. A set of genes that regulate the nitric oxide and dopamine signaling pathways in Drosophila have been implicated in tracheal development by virtue of the tracheal phenotypes of mutants and the expression of the gene products in developing trachea. These genes are (1) Punch, encoding GTP cyclohydrolase, the rate-limiting enzyme in tetrahydrobiopterin cofactor synthesis, (2) pale, endoding tyrosine hydroxylase, the rate-limiting enzyme in dopamine biosynthesis, and (3) Catecholamines up, encoding a transmembrane protein that negatively regulates both GTP cyclohydrolase and tyrosine hydroxylase. It is proposed that dopamine regulates the fibroblast growth factor receptor ortholog, Breathless, and that the regulating genes also interact with nitric oxide synthase (also a tetrahydrobiopterin-requiring enzyme) in the branch outgrowth that occurs in response to hypoxia. The Specific Aims of the project are (1) to conduct gene interaction studies to define dopamine and nitric oxide participation in tracheogenesis, (2) to test the hypothesis that catecholamine signaling down-regulates FGF-Receptor, and (3) to investigate the roles of these interacting genes in hypoxia-sensitive terminal branching. These pathways have been extensively investigated in other, contexts with the use of a wide range of pharmacological agents, and it is likely that these findings could translate readily into candidates for angiogenesis intervention therapies.