Tracheal Development in Drosophila: Angiogenic models

描述（由申请人提供）果蝇中的气管（一种管状网络）的发育是血管生成的模型，具有许多在哺乳动物血管生成中具有对应物的气管调节基因产物。血管生长的调节在实体瘤的生长和维持以及非实体瘤恶性肿瘤的进展中具有关键作用。通过突变体的气管表型和基因产物在发育中的气管中的表达，一组调节果蝇中一氧化氮和多巴胺信号通路的基因已被牵连在气管发育中。这些基因是（1）Punch，编码GTP环化水解酶，四氢生物蝶呤辅因子合成中的限速酶，（2）pale，内源性酪氨酸羟化酶，多巴胺生物合成中的限速酶，和（3）儿茶酚胺向上，编码负调节GTP环化水解酶和酪氨酸羟化酶的跨膜蛋白。有人提出，多巴胺调节成纤维细胞生长因子受体的直系同源物，气喘吁吁，和调节基因也相互作用，与一氧化氮合酶（也是四氢生物蝶呤需要酶）的分支生长，发生在缺氧。该项目的具体目的是（1）进行基因相互作用研究，以确定多巴胺和一氧化氮参与气管发生，（2）测试儿茶酚胺信号下调FGF受体的假设，（3）研究这些相互作用的基因在缺氧敏感的末端分支中的作用。这些途径已在其他背景下使用广泛的药理学试剂进行了广泛的研究，这些发现可能很容易转化为血管生成干预疗法的候选药物。

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.