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Control of Anoxia-Reoxygenation Responses by the O2-sensing Enzyme EGL-9 Pathway

O2 感应酶 EGL-9 途径控制缺氧-复氧反应

基本信息

批准号：
8700065
负责人：
Dengke Ma
金额：
$ 6.59万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2015-01-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8700065
关键词：
Adult Affect Animal Behavior Animal Feed Animals Anoxia Area Behavior Behavioral Behavioral Model Bioenergetics Biological Biological Assay Biology Blood flow Caenorhabditis elegans Candidate Disease Gene Cell Survival Cell model Cells Cessation of life Chemicals Computers Critical Pathways Cytochrome P450 Developed Countries Disease Disseminated Malignant Neoplasm Eicosanoids Employee Strikes Enzymes Escherichia coli Exhibits Experimental Models Failure Family Gases Gene Targeting Genes Genetic Genetic Screening Goals Habitats Homeostasis Homologous Gene Human Hypoxia Hypoxia Inducible Factor Injury Ischemia Ischemic Stroke Laboratory Research Link Locomotion Mammals Mediating Medical Mentors Mixed Function Oxygenases Modeling Molecular Morbidity - disease rate Movement Mutagenesis Mutation Myocardial Infarction Myocardial Ischemia Myocardial Reperfusion Injury Nematoda Neurons Organ failure Organism Oxidative Stress Oxygen Oxygenases Pathway interactions Phase Physiology Process Procollagen-Proline Dioxygenase Proteins Public Health RNA Interference Reactive Oxygen Species Regulation Reperfusion Injury Reperfusion Therapy Research Series Signaling Molecule Solid Neoplasm Speed Stroke Suppressor Mutations System Testing Tissues Training Support United States base behavior influence career cell growth cell injury deprivation gene cloning genome sequencing genome-wide hypoxia inducible factor 1 mortality mutant neoplastic cell new therapeutic target novel preconditioning prevent research study response response to injury restoration skills tool transcription factor transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Anoxia (lack of oxygen) followed by reoxygenation causes severe detrimental effects in a wide variety of medical conditions, including ischemic reperfusion injury and myocardial infarction. How animals sense anoxia- reoxygenation and prevent tissue injury are fundamental and unanswered issues. The transcription factor hypoxia inducible factor (HIF) is a key cell protector against anoxia-reoxygenation (A/R)-induced injury. The discovery of the C. elegans gene egl-9, which encodes an O2-sensing prolyl hydroxylase of HIF-1, has led to the identification of an evolutionarily conserved pathway central for maintaining O2 homeostasis in organisms from nematodes to humans. Inhibition of mammalian HIF hydroxylase homologs of EGL-9 strongly protects from myocardial ischemia and reperfusion injury. Using automated behavioral tracking under conditions of changing O2 concentrations, I discovered a locomotary behavior called the O2-ON response and have shown that the O2-ON response can model key aspects of mammalian tissue response to ischemia-reperfusion injury. EGL-9 is essential for the O2-ON response and mediates the effect of hypoxic preconditioning on the suppression of the O2-ON response. From a series of genetic screens, I discovered CYSL-1 as a new regulator of EGL-9 and a Cytochrome P450 enzyme that generates eicosanoid signaling molecules downstream of EGL-9 to control the O2-ON response. I also isolated C. elegans mutants that define additional novel regulators and targets of the EGL-9/HIF-1 pathway. The overall goal of this project is to clone the genes defined by these mutants and identify the novel conserved regulators of biological responses to A/R, which is modulated by the EGL-9 pathway, and determine the underlying molecular and cellular mechanisms. In the K99 phase of this project, I will establish and characterize C. elegans behavioral and cellular models for ischemia-reperfusion injury. In the R00 phase of this project, I will further determine the key mechanisms by which A/R causes the O2-ON response and identify novel conserved regulators and targets of the EGL-9 pathway, which mediates protection from A/R-induced cellular injury and behavioral response to A/R. Using combined molecular, cellular and behavioral analyses together with powerful genetic screens, I will systematically dissect the genetic pathways and define the fundamental mechanisms that regulate cellular and animal responses to A/R. With the support of and training opportunities provided by K99/R00, I plan to expand my current experimental and intellectual skills and develop expertise in areas of O2-related biology and diseases, which is vital to my career goal of directing an independent and successful research laboratory.

描述（由申请人提供）：缺氧（缺氧）后再给氧会对多种医学疾病（包括缺血性再灌注损伤和心肌梗死）造成严重的有害影响。动物如何感知缺氧-复氧并防止组织损伤是一个基本而未解决的问题。转录因子缺氧诱导因子（HIF）是一种重要的细胞保护因子，可保护细胞免受缺氧-复氧（A/R）损伤。C. elegans基因egl-9编码HIF-1的O2敏感脯氨酰羟化酶，已经鉴定出一种进化上保守的途径，从线虫到人类的有机体中的O2稳态。EGL-9的哺乳动物HIF羟化酶同源物的抑制强烈地保护免于心肌缺血和再灌注损伤。在改变O2浓度的条件下使用自动行为跟踪，我发现了一种称为O2-ON反应的非线性行为，并表明O2-ON反应可以模拟哺乳动物组织对缺血再灌注损伤反应的关键方面。EGL-9是O2-ON反应所必需的，并介导低氧预处理对O2-ON反应的抑制作用。从一系列的遗传筛选中，我发现CYSL-1是EGL-9的一种新的调节剂，也是一种细胞色素P450酶，在EGL-9下游产生类花生酸信号分子，以控制O2-ON反应。我也分离出了C。elegans突变体，定义了EGL-9/HIF-1途径的其他新的调节因子和靶点。该项目的总体目标是克隆这些突变体定义的基因，并确定由EGL-9途径调节的A/R生物反应的新型保守调节因子，并确定潜在的分子和细胞机制。在本项目的K99阶段，我将建立和表征C。elegans缺血再灌注损伤的行为和细胞模型。在该项目的R 00阶段，我将进一步确定A/R引起O2-ON反应的关键机制，并确定EGL-9通路的新保守调节因子和靶点，EGL-9通路介导对A/R诱导的细胞损伤和对A/R的行为反应的保护。结合分子，细胞和行为分析以及强大的遗传筛选，我将系统地剖析遗传途径，并定义调节细胞和动物对A/R反应的基本机制。通过K99/R 00提供的支持和培训机会，我计划扩大我目前的实验和智力技能，并在O2相关生物学和疾病领域发展专业知识，这对我指导独立和成功的研究实验室的职业目标至关重要。