Genetic Dissection of Hypoxia Tolerance

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Hypoxia, whether present during physiologic states (e.g., embryogenesis and organ formation) or during pathologic states (e.g., asthma, chronic obstructive lung disease, obstructive sleep apnea, sickle cell anemia), present a challenge to the organism. Depending on duration and severity, hypoxia can lead to cell injury and death and consequently organ injury and failure. This is well illustrated in diseases that lead to major morbidity and mortality, such as myocardial infarct, cerebro-vascular accidents and dysfunction, and placental insufficiency with poor development or demise. We have previously discovered that the adult Drosophila melanogaster, is acutely tolerant to a low O2 environment, withstanding -3-4 hours of total O2 deprivation without showing any evidence of cell injury. Subsequently, our laboratory embarked on the study of hypoxia tolerance and mutagenesis and overexpression screens were begun to investigate loss- or gain-of-function phenotypes. Both have given us promising results and, in this application, we take advantage of both approaches to address the aims in this proposal. For example, we have succeeded during the past 6-7 years in generating a fly strain, through experimental selection, that can perpetuate through all of Its life cycle stages in low O2 environments. Through microarrays and sophisticated bio-informatic analyses, we have obtained genes (e.g., Notch pathway genes) that play an important role in hypoxia resistance. This Project centers on the responses of Drosophila to acute (hours) and chronic (days) hypoxia as well as in selected flies under hypoxia pressure and on the role of the Notch pathway in hypoxia tolerance and susceptibility. The overall goal and long term objective in this Project will be to render hypoxia-sensitive cells and tissues, such as those in mammals, much more resistant to low 02. The specific hypotheses are: 1) The Notch pathway and Its target genes play an important role in the remarkable ability of a laboratory-selected D. melanogaster to perpetuate in low O2 environments. 2) The Notch-Toll interactions are critical for hypoxia tolerance and have different roles in development in the hypoxia-selected flies. 3) The Notch pathway regulates hypoxia susceptibility and tolerance in mammalian tissues/cells. We believe that the proposed experiments will allow us to gain insight regarding susceptibility and tolerance to low 02 and will therefore pave the way to develop better therapies for ailments that afflict humans as a consequence of low 02 delivery or blood 02 levels.