Genetic Dissection of Hypoxia Tolerance

耐缺氧的基因剖析

基本信息

批准号：
8001408
负责人：
Gabriel G Haddad
金额：
$ 40.24万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8001408
关键词：
Acute Address Adult Aging Alcohols Anoxia Applications Grants Asthma Biomedical Engineering Cells Cerebrum Cessation of life Chronic Development Disease Dissection Drosophila genus Drosophila melanogaster Electron Microscopy Embryonic Development Environment Failure Fetal Development Gene Targeting Generations Genes Genetic Genome Goals Hour Hypoxia Injury Invertebrates Investigation Laboratories Lead Life Life Cycle Stages Light Lung diseases Malignant Neoplasms Mammalian Cell Mediating Modeling Molecular Morbidity - disease rate Mus Mutagenesis Myocardial Myocardial Ischemia Names Neuraxis Organ Organelles Organism Pathologic Pathology Pathway interactions Phenotype Phosphorus Physiological Placental Insufficiency Play Predisposition Process Recording of previous events Resistance Role Severities Sickle Cell Anemia Signal Transduction Sleep Apnea Syndromes Stroke Testing The Sun Tissue Survival Tissues Vertebrates base cell injury comparative deprivation fly human disease loss of function man mortality mutant new therapeutic target notch protein positional cloning pressure research study response stem

项目摘要

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.

缺氧，无论是在生理状态（例如胚胎发生和器官形成）还是在病理状态下（例如哮喘、慢性阻塞性肺病、阻塞性睡眠呼吸暂停、镰状细胞病贫血），对机体提出了挑战。根据持续时间和严重程度，缺氧可能会导致细胞伤害和死亡以及随后的器官损伤和衰竭。这在导致以下疾病的疾病中得到了很好的说明：主要发病率和死亡率，如心肌梗塞、脑血管意外和功能障碍，以及胎盘功能不全，发育不良或死亡。我们之前发现，成年果蝇对低浓度有很强的耐受性。 O2 环境，可承受 -3-4 小时的完全缺氧，而不会出现任何细胞损伤的迹象。随后，我们实验室开始了耐缺氧及诱变和过表达的研究开始进行筛选以研究功能丧失或获得功能的表型。两者都给了我们有希望的结果，在这个应用中，我们利用这两种方法来实现这个目标提议。例如，在过去的 6-7 年里，我们通过实验选择，可以在低 O2 环境中贯穿其生命周期的所有阶段。通过微阵列和复杂的生物信息学分析，我们获得了基因（例如，Notch 途径基因）在耐缺氧中发挥重要作用。该项目集中于以下方面的回应果蝇急性（小时）和慢性（天）缺氧以及处于缺氧压力下的选定果蝇以及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该项目的目标是使缺氧敏感的细胞和组织，例如哺乳动物中的细胞和组织，对低02的抵抗力更强。具体假设是：1）Notch通路及其靶点基因在实验室选择的黑腹果蝇的卓越能力中发挥着重要作用在低 O2 环境中持续存在。 2) Notch-Toll 相互作用对于耐缺氧至关重要并且在缺氧选择的果蝇的发育中具有不同的作用。 3）Notch通路调节哺乳动物组织/细胞的缺氧敏感性和耐受性。我们认为，拟议的实验将使我们能够深入了解对低 02 的敏感性和耐受性，因此为开发更好的疗法来治疗因 02 低而困扰人类的疾病铺平道路分娩或血液02水平。