O2-CHEMOSENSING BY REATIVE OXYGEN SPECIES/NADPH OXIDASE

通过活性氧/NADPH 氧化酶进行 O2 化学传感

基本信息

批准号：
7473888
负责人：
SALVATORE J FIDONE
金额：
$ 29.5万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
1978
资助国家：
美国
起止时间：
1978-07-01 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7473888
关键词：
Acute Animals Attention Carotid Body Cell Hypoxia Cell Proliferation Cell physiology Cells Chemicals Chemoreceptors Chronic Chronic Obstructive Airway Disease Complex Condition Coupling Data Depressed mood Endothelin Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Evaluation Exposure to Fluorescent Dyes Future Gene Deletion Generations Glomus Cell Goals Homologous Gene Hypoxia Imaging Techniques In Vitro Laboratories Localized Lung Lung diseases Mediating Membrane Messenger RNA Methods Mus NADP NADPH Oxidase Nerve Neuroectoderm Neuroepithelial Bodies Neurotransmitters Nodose Ganglion Oxidases Oxygen Pathway interactions Pentosephosphate Pathway Physiological Physiological Adaptation Play Potassium Channel Preparation Production Protein Overexpression Proteins Publishing Range Rattus Reactive Oxygen Species Research Research Design Respiratory Burst Rest Reverse Transcriptase Polymerase Chain Reaction Role Signal Transduction Sleep Apnea Syndromes Slice Source Structure of superior cervical ganglion Techniques Testing Tissues Transcript Transgenic Mice Type I Epithelial Receptor Cell Vascular Endothelial Growth Factors carotid sinus catalase cellular imaging dihydroethidium inhibitor/antagonist innovation neutrophil programs research study response

项目摘要

DESCRIPTION (provided by applicant): O2-sensing in the carotid body occurs in neuroectoderm-derived type I glomus cells where hypoxia elicits a complex chemotransduction cascade involving membrane depolarization, Ca 2+ entry and the release of excitatory neurotransmitters. Efforts to understand the exquisite O2-sensitivity of these cells focus primarily on the relationship between PO2 and the activity of K+-channels. A current hypothesis proposes that coupling between local PO2 and the open-closed state of K+-channels is mediated by a phagocytic-like multisubunit enzyme, NADPH oxidase, which produces reactive oxygen species (ROS) in proportion to the prevailing PO2. In O2-sensitive cells contained in lung neuroepithelial bodies (NEB), experiments have confirmed that ROS levels decrease in hypoxia, and that E M and K+-channel activity are indeed controlled by ROS produced by NADPH oxidase. However, recent studies in our laboratory suggest that ROS generated by a non-phagocytic form of NADPH oxidase, are important contributors to chemotransduction, but that their role in type I cells differs fundamentally from the mechanism utilized by NEB. We propose to test the hypothesis that in response to hypoxia, NADPH oxidase activity is increased in type I cells, and further, that increased ROS levels generated in response to low-O2 facilitate membrane re-polarization via the activation of a subset of K+-channels. In addition, we will examine the hypothesis that a non-phagocytic NADPH oxidase mediates adaptive morphological and physiological adjustments induced by exposure of the carotid body to chronic hypoxia (CH), a condition that occurs clinically in sleep apnea and chronic obstructive pulmonary disease (COPD). Studies will include: I. An examination of the sources and mechanisms of ROS production in type I cells, II. Evaluation of the involvement of NADPH oxidase and ROS in the carotid body response to acute hypoxia; III. The expression of NADPH oxidase subunits in the carotid body; and the effects of CH; and IV. The role of NADPH oxidase and ROS in carotid body adaptation to CH.

描述（由申请人提供）：颈动脉体内的O2敏感性发生在神经脱皮的I型Glomus细胞中，其中缺氧引起复杂的趋化性转导级联级联反应，涉及膜去极化，Ca 2+进入，并释放兴奋性神经功能激素。理解这些细胞的精致O2敏感性的努力主要集中于PO2与K+通道活性之间的关系。当前的假设提出，局部PO2与K+通道的开放闭合状态之间的耦合是由一种吞噬细胞样的多生育酶，NADPH氧化酶介导的，NADPH氧化酶，该酶以与普遍的PO2成正比产生活性氧（ROS）。在肺神经上皮体（NEB）中包含的O2敏感细胞中，实验证实了ROS水平降低了缺氧，而E M和K+通道活性确实由NADPH氧化酶产生的ROS控制。然而，在我们的实验室中的最新研究表明，由非氧化酶的非变形细胞形式产生的ROS是趋化性转导的重要因素，但是它们在I型细胞中的作用与NEB所利用的机制有所不同。我们建议测试以下假设：对于缺氧，NADPH氧化酶活性在I型细胞中增加了，此外，该假设增加了对低O2响应的ROS水平，从而促进了通过激活K+ - 通道的激活膜重新化。此外，我们将研究以下假设：非形态细胞NADPH氧化酶介导颈动脉体暴露于慢性缺氧（CH）引起的适应性形态学和生理调整，这种疾病在睡眠呼吸暂停中临床上发生在临床上，慢性阻塞性肺部疾病（COPD）。研究将包括：I。对I型细胞中ROS产生的来源和机制的检查，ii。评估NADPH氧化酶和ROS参与颈动脉身体对急性缺氧的反应； iii。颈动脉体内NADPH氧化酶亚基的表达；以及CH的影响；和IV。 NADPH氧化酶和ROS在颈动脉体适应CH中的作用。