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：
9211377
负责人：
Dengke Ma
金额：
$ 24.6万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9211377
关键词：
Adult Animal Behavior Animals Anoxia Behavior Behavioral Behavioral Model Biological Caenorhabditis elegans Cardiovascular system Cells Cessation of life Collaborations Cytochrome P450 Cytochrome a Developed Countries Disease Eicosanoids Environment Enzymes Fostering Genes Genetic Screening Goals Homeostasis Human Hypoxia Hypoxia Inducible Factor Injury Lead Mediating Medical Metabolic Mixed Function Oxygenases Modeling Molecular Morbidity - disease rate Myocardial Infarction Myocardial Ischemia Myocardial Reperfusion Injury Nematoda Organ failure Organism Oxygen Pathway interactions Phase Physiology Procollagen-Proline Dioxygenase Reperfusion Injury Research Research Institute Series Signaling Molecule Tissues Training Support United States behavioral response cell injury hypoxia inducible factor 1 mortality mutant new therapeutic target novel novel therapeutics preconditioning prevent response response to injury transcription factor transcriptome sequencing

项目摘要

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 injui^. The discovery of the C. elegans gene egl-9, which encodes an 02-sensing prolyl hydroxylase of HIF- 1, has led to the identification of an evolutionarily conserved pathway central for maintaining 02 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 02 concentrations, I discovered a locomotory behavior called the 02-ON response and have shown that the 02-ON response can model key aspects of mammalian tissue response to ischemia-reperfusion injury. EGL-9 is essential for the 02-ON response and mediates the effect of hypoxic preconditioning on the suppression of the 02-ON response. From a series of genetic screens, I discovered CYSL-1 as a new regulator of EGL-9 and a Cytochrome P450 enzyme CYP-13A12 that generates eicosanoid signaling molecules downstream of EGL-9 to control the 02-ON response. I also performed RNA-seq and 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 identify and characterize 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 have established behavioral and cellular C. elegans models for ischemia-reperfusion injury and characterized CYP-13A12 as a PUFA-epoxygenase in controlling the 02-ON response. In the ROO phase of this project, I will further determine the key mechanisms by which A/R causes the 02-ON response and identify novel regulators and targets of the EGL-9 pathway, which mediates protection from A/R-induced cellular injury and behavioral response to A/R. In my new independent lab in the Cardiovascular Research Institute and Department of Physiology at UCSF in the ROO phase, the outstanding scientific environment will enable me to achieve the research goals and also foster my intellectual interaction and potential collaboration with both biologists and clinicians to seek how identified genes and mechanisms lead to new therapeutics in metabolic and ischemic human disorders. The training and support provided by K99/R00 will facilitate my transition into a fully independent and successful PI.

缺氧（缺氧）和随后的复氧会对多种疾病造成严重的有害影响医疗状况，包括缺血性再灌注损伤和心肌梗塞。动物如何感知缺氧-复氧和防止组织损伤是根本且尚未解决的问题。转录缺氧诱导因子 (HIF) 是抵抗缺氧复氧 (A/R) 诱导的关键细胞保护因子因吉^.线虫基因egl-9的发现，该基因编码HIF-的02感应脯氨酰羟化酶 1，导致了对维持 02 稳态的核心进化保守途径的鉴定从线虫到人类的生物体中。 EGL-9 的哺乳动物 HIF 羟化酶同系物的抑制强烈保护心肌免受缺血和再灌注损伤。使用自动行为跟踪在改变 02 浓度的条件下，我发现了一种称为 02-ON 的运动行为反应并表明 02-ON 反应可以模拟哺乳动物组织反应的关键方面致缺血再灌注损伤。 EGL-9 对于 02-ON 反应至关重要，并介导缺氧的影响 02-ON 响应抑制的预处理。从一系列的基因筛查中，我发现 CYSL-1 作为 EGL-9 和细胞色素 P450 酶 CYP-13A12 的新调节剂，可产生 EGL-9 下游的类二十烷酸信号分子控制 02-ON 反应。我也表演过 RNA-seq 和分离的秀丽隐杆线虫突变体定义了 EGL- 的其他新型调节因子和靶标 9/HIF-1 途径。该项目的总体目标是识别和表征新颖的保守基因 A/R 生物反应的调节因子，由 EGL-9 途径调节，并确定潜在的分子和细胞机制。在这个项目的K99阶段，我建立了线虫缺血再灌注损伤的行为和细胞模型，并将 CYP-13A12 描述为 PUFA-环氧合酶控制02-ON反应。在这个项目的ROO阶段，我将进一步确定 A/R 引起 02-ON 响应的关键机制并确定新型调节剂和 EGL-9 通路的靶点，介导针对 A/R 诱导的细胞损伤和行为的保护对应收帐款的响应。在我位于心血管研究所和系的新独立实验室中 UCSF生理学处于ROO阶段，优秀的科学环境将使我能够实现研究目标，也促进我与生物学家和科学家的智力互动和潜在合作临床医生寻找已识别的基因和机制如何导致代谢和缺血的新疗法人类失调。 K99/R00 提供的培训和支持将帮助我过渡到完全独立且成功的 PI。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Conserved roles of C. elegans and human MANFs in sulfatide binding and cytoprotection.

线虫和人类 MANF 在硫苷脂结合和细胞保护中的保守作用。

DOI：
发表时间：
2018-03-01
期刊：
影响因子：
16.6
作者：
Bai, Meirong;Vozdek, Roman;Hnízda, Aleš;Jiang, Chenxiao;Wang, Bingying;Kuchar, Ladislav;Li, Tiejun;Zhang, Yuefan;Wood, Chase;Feng, Liang;Dang, Yongjun;Ma, Dengke K
通讯作者：
Ma, Dengke K

CYSL-1 interacts with the O2-sensing hydroxylase EGL-9 to promote H2S-modulated hypoxia-induced behavioral plasticity in C. elegans.

CYSL-1 与 O2 感应羟化酶 EGL-9 相互作用，促进线虫中 H2S 调节的缺氧诱导的行为可塑性。

DOI：
发表时间：
2012-03-08
期刊：
影响因子：
16.2
作者：
Ma, Dengke K;Vozdek, Roman;Bhatla, Nikhil;Horvitz, H Robert
通讯作者：
Horvitz, H Robert

Cytochrome P450 drives a HIF-regulated behavioral response to reoxygenation by C. elegans.

细胞色素 P450 驱动线虫对复氧的 HIF 调节行为反应。

DOI：
发表时间：
2013-08-02
期刊：
影响因子：
0
作者：
Ma, Dengke K;Rothe, Michael;Zheng, Shu;Bhatla, Nikhil;Pender, Corinne L;Menzel, Ralph;Horvitz, H Robert
通讯作者：
Horvitz, H Robert

The receptor tyrosine kinase HIR-1 coordinates HIF-independent responses to hypoxia and extracellular matrix injury.

受体酪氨酸激酶 HIR-1 协调 HIF 独立的缺氧和细胞外基质损伤反应。