Tracheal Development in Drosophila: Angiogenic models

描述(由申请人提供)果蝇的气管发育是一个管状网络，是血管生成的模型，许多气管调节基因产物与哺乳动物的血管生成具有对应关系。血管突起的调控在实体肿瘤的生长和维持以及非实体肿瘤的进展中起着至关重要的作用。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，一组调控果蝇体内一氧化氮和多巴胺信号通路的基因被认为与气管发育有关。这些基因是(1)Punch，编码GTP环水解酶，是四氢生物蝶呤辅因子合成的限速酶；(2)苍白的内含型酪氨酸羟基酶，多巴胺生物合成的限速酶；(3)儿茶酚胺，编码一种跨膜蛋白，对GTP环水解酶和酪氨酸羟基酶都有负面调节作用。有人认为，多巴胺调节成纤维细胞生长因子受体的同源基因Breathless，并且调节基因还与分支中的一氧化氮合酶(也是一种四氢生物蝶呤需要酶)相互作用，该酶发生在对低氧的反应中。该项目的具体目标是(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的作用；(2)检验儿茶酚胺信号下调成纤维细胞生长因子受体的假说；(3)研究这些相互作用基因在低氧敏感的末端分支中的作用。这些途径已经在其他情况下进行了广泛的研究，并使用了广泛的药理学药物，这些发现很可能很容易转化为血管生成干预疗法的候选者。

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.