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.
