NITRIC OXIDE AND RESPONSES TO HYPOXIA IN DROSOPHILA

一氧化氮和果蝇对缺氧的反应

• 批准号: 6363342
• 负责人: PATRICK H O'FARRELL
• 金额: $ 32.52万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2004-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6363342
• 关键词: Drosophilidae; behavioral /social science research tag; biological signal transduction; cell cycle; exploratory behavior; genetic screening; growth inhibitors; hypoxia; invertebrate embryology; mutant; nitric oxide

Oxygen is essential to many forms of life. Shortfalls in oxygen supply (hypoxia) can be deleterious. Damage resulting from local hypoxia, as occurs in stroke, influences human health. Cellular and whole-organism adaptations to hypoxia occur in species from bacteria to humans. We propose to study the mechanisms of the responses to hypoxia in a model experimental organism, Drosophila. In preliminary work, we have shown that hypoxia induces an exploratory behavior in larvae, and arrests the cell cycle. These responses can also be induced by nitric oxide (NO) and suppressed by NO inhibitors. Hence, NO, a known mammalian signaling molecule that can increase blood flow to hypoxic tissues by promoting vasodilation, has a role in responding to hypoxia in flies too. We propose genetic and molecular approaches to dissect the response pathway and to explore the role of NO. We will screen for mutants that fail to survive hypoxia. Since the response promotes survival, hypoxia sensitive mutants will include mutants in the response to hypoxia. Phenotypic analysis will be used to classify mutants, and mutant classes affecting processes of interest will be examined in detail. We will focus on mutations that are defective in sensing oxygen or those that are altered in cell cycle or behavioral responses to hypoxia. Molecular studies using transgenes, drugs and mutations will probe the mechanisms that arrest cell cycle progression. Similar tools will be developed to dissect the signal transduction pathway that provokes adaptive changes in behavior and cell cycle progression in response to reduced oxygen.

氧气对于许多生命形式至关重要。 氧气供应不足（缺氧）可能是有害的。 局部缺氧造成的损害（如中风）会影响人类健康。 从细菌到人类，细胞和整个生物体对缺氧的适应发生在各种物种中。 我们建议研究模型实验生物果蝇对缺氧的反应机制。 在初步工作中，我们已经证明缺氧会诱导幼虫的探索行为，并阻止细胞周期。 这些反应也可由一氧化氮 (NO) 诱导并被 NO 抑制剂抑制。 因此，NO这种已知的哺乳动物信号分子可以通过促进血管舒张来增加流向缺氧组织的血流量，它在果蝇的缺氧反应中也发挥着作用。 我们提出遗传和分子方法来剖析反应途径并探索 NO 的作用。 我们将筛选无法在缺氧条件下生存的突变体。 由于反应促进生存，缺氧敏感突变体将包括对缺氧反应的突变体。表型分析将用于对突变体进行分类，并且将详细检查影响感兴趣过程的突变体类别。 我们将重点关注氧气感知缺陷的突变或细胞周期或对缺氧的行为反应发生改变的突变。 使用转基因、药物和突变的分子研究将探讨阻止细胞周期进展的机制。 将开发类似的工具来剖析信号转导途径，该途径会响应减少的氧气而引发行为和细胞周期进展的适应性变化。