Genetic Dissection of Hypoxia Tolerance

缺氧，无论是否存在于生理状态期间（例如，胚胎发生和器官形成）或 在病理状态期间（例如，哮喘，慢性阻塞性肺疾病，阻塞性睡眠呼吸暂停，镰状细胞 贫血），对机体提出挑战。根据持续时间和严重程度，缺氧可导致细胞 损伤和死亡，以及随后的器官损伤和衰竭。这一点在导致 主要发病率和死亡率，如心肌梗死、心血管意外和功能障碍，以及 胎盘发育不全或死亡。 我们先前已经发现，成年黑腹果蝇，是急性耐受低， O2环境，承受约3 - 4小时的总O2剥夺，而没有显示出任何细胞损伤的证据。 随后，本实验室开展了耐缺氧及突变和过表达的研究 开始筛选以研究功能丧失或获得的表型。他们都给了我们 有希望的结果，在这个应用程序中，我们利用这两种方法来解决这个目标， 提议例如，在过去的6-7年里，我们成功地产生了一种蝇种， 实验选择，可以在低O2环境中延续整个生命周期阶段。 通过微阵列和复杂的生物信息学分析，我们已经获得了基因（例如，凹口 途径基因）在耐缺氧中起重要作用。本项目的重点是 果蝇对急性（小时）和慢性（天）缺氧以及在选定的苍蝇缺氧压力 以及Notch通路在缺氧耐受性和易感性中的作用。总体目标和长远目标 本项目的目标是使缺氧敏感细胞和组织，如哺乳动物中的细胞和组织， 更能抵抗低氧气。具体的假说有：1）Notch通路及其靶点 基因在实验室选育的D.黑腹至 在低O2环境中持续存在。2)Notch-Toll相互作用对缺氧耐受性至关重要 并且在低氧选择性果蝇的发育中具有不同的作用。3)Notch途径调节 哺乳动物组织/细胞缺氧敏感性和耐受性。我们相信建议的 实验将允许我们获得关于对低O2的敏感性和耐受性的了解 为开发更好的治疗方法铺平道路，这些疾病因低O2而折磨人类。 输注或血液氧含量。

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.