Mechanisms of Oxygen Sensing

氧传感机制

基本信息

批准号：
8604410
负责人：
NAVDEEP S CHANDEL
金额：
$ 18.62万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-15 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8604410
关键词：
Acute Lung Injury Address Affinity Chromatography Binding Biology Cardiovascular Diseases Cardiovascular system Catalytic Domain Cells Chronic Chronic Obstructive Airway Disease Clinic Complex Cysteine Data Disease Electron Transport Complex III Environmental air flow Erythropoiesis Fibrosis Gene Targeting Generations Genetic Programming Glycolysis Grant Health Homeostasis Hydroxylation Hypertension Hypertrophy Hypoxemia Hypoxia Inflammation Knowledge Lead Life Lung Lung diseases Malignant Neoplasms Malignant neoplasm of lung Medial Mediator of activation protein Mitochondria Mixed Function Oxygenases Molecular Muscular Atrophy Oxygen Pathology Pathway interactions Patients Pharmaceutical Preparations Phosphoric Monoester Hydrolases Phosphotransferases Post-Translational Protein Processing Procollagen-Proline Dioxygenase Protein Binding Protein Subunits Proteins Proteomics Pulmonary Fibrosis Pulmonary Hypertension Pulmonary artery structure Pulmonary vessels Reactive Oxygen Species Research Response Elements Role Signaling Molecule Tertiary Protein Structure Testing Ubiquitination Up-Regulation angiogenesis base constriction new therapeutic target novel oxidation programs promoter public health relevance reconstitution response sensor therapeutic target transcription factor ubiquitin ligase vector

项目摘要

DESCRIPTION (provided by applicant): Oxygen homeostasis is essential for life and health, including pulmonary and cardiovascular health. Chronic hypoxia is associated with a myriad of pathologies including pulmonary related diseases such as COPD, lung cancer, pulmonary hypertension, fibrosis and inflammation. Research on oxygen sensing pathways has revealed important mediators of oxygen homeostasis, however, detailed knowledge of the molecular mechanisms of oxygen sensing remain uncovered. Fuller understanding of the cellular oxygen sensing pathways may lead to identification of novel therapeutic targets for treatment of pulmonary and cardiovascular disease. At the cellular level, hypoxia activates the Hypoxia Inducible transcription Factors (HIFs). HIFs bind to hypoxia-response elements in the promoter/enhance regions of a large number of target genes resulting in activation of a genetic program that includes upregulation of glycolysis, angiogenesis, and erythropoiesis. Under normoxic conditions, the HIF¿ protein subunit is hydroxylated by Prolyl Hydroxylase Domain protein 2 (PHD2), targeting it for ubiquitination by the von Hippel-Lindau (VHL) ubiquitin ligase, and proteasomal degradation. The activity of PHD2 is inhibited under hypoxic conditions, allowing the accumulation of HIF¿ protein and the subsequent binding to HIF¿ subunit to induce the transcriptional response. The underlying mechanism by which oxygen levels diminish PHD2 activity is not fully understood. We have previously demonstrated that hypoxia increases the generation of ROS from mitochondrial complex III resulting in inhibition of HIF¿ protein hydroxylation and subsequent HIF¿ protein stabilization. In this proposal we will utilize a proteomic approach to test whether hypoxia-induced mitochondrial ROS lead to inhibition of PHD2 activity by binding of unidentified proteins, post-translational modification of PHD2, and/or oxidizing of cysteine residues within PHD2. Currently, there have been no successful drugs in the clinic targeting inhibition of HIFs. This exploratory grant will provide detailed understanding of how PHD2 is regulated during hypoxia leading to rationale molecular basis for therapeutic targeting of HIFs.

描述（由适用提供）：氧气稳态对于生活和健康至关重要，包括肺部和心血管健康。慢性缺氧与多种病理有关，包括肺相关疾病，例如COPD，肺癌，肺动脉高压，纤维化和感染。关于氧气传感途径的研究揭示了氧气稳态的重要介质，但是，仍然发现了氧气传感分子机制的详细知识。对细胞氧气传感途径的全面了解可能导致鉴定出新的热靶标，以治疗肺和心血管疾病。在细胞水平上，缺氧激活缺氧诱导的转录因子（HIF）。 HIF与大量靶基因的启动子/增强区域中的缺氧 - 反应元件结合，导致激活遗传程序，其中包括上调糖酵解，血管生成和红细胞生成。在常氧条件下，HIF？蛋白亚基由羟基羟化酶结构蛋白2（PHD2）羟基亚基，靶向von Hippel-lindau（VHL）泛素蛋白系列酶和蛋白酶体降解。 PHD2的活性在低氧条件下抑制，从而允许HIF蛋白的积累以及随后与HIF hif subunit的结合以诱导转录反应。氧气水平降低PHD2活性的基本机制尚不完全了解。我们先前已经证明，缺氧会增加线粒体复合物III的ROS产生，从而抑制HIF。蛋白质羟基化和随后的HIF蛋白稳定化。在该提案中，我们将利用一种蛋白质组学方法来测试缺氧诱导的线粒体ROS是否通过结合统一蛋白的结合，PHD2的翻译后修饰和/或氧化PHD2中的膀胱保留剂是否导致PHD2活性抑制。目前，针对HIF的临床临床中没有成功的药物。该探索性赠款将提供详细的理解在缺氧期间如何调节PHD2，从而导致HIF治疗靶向的基本原理基础。