Cyclooxygenase 2 and Ischemic Neuronal Injury

环氧合酶 2 与缺血性神经元损伤

基本信息

批准号：
7233670
负责人：
STEVEN H GRAHAM
金额：
$ 33.44万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-06-01 至 2008-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7233670
关键词：
9-deoxy-delta-9-prostaglandin D2 Accounting Address Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Anoxia Antioxidants Apoptosis Arachidonic Acids Autoradiography Binding Blood Vessels Blood flow Brain Brain Hypoxia-Ischemia Carbon Cell Death Cerebral Ischemia Cessation of life Consumption Coxibs Data Disease Enzymes Funding Genes Hypoxia In Vitro Infarction Inflammatory Injury Ischemia Ischemic Neuronal Injury Lead Ligands Measures Motor Neurons Mus Neurodegenerative Disorders Neurons Oxidative Stress PPAR gamma Pathogenesis Peroxidase Peroxidases Peroxisome Proliferator-Activated Receptors Play Production Prostaglandin H2 Prostaglandin Production Prostaglandin-Endoperoxide Synthase Prostaglandins Protein Isoforms Protein Overexpression Rattus Receptor Activation Resistance Role Stroke Synapses Testing Thinking Wild Type Mouse ascorbate base cyclooxygenase 1 cyclooxygenase 2 cyclopentenone design fatty acid oxidation fetal in vivo inhibitor/antagonist injured iodoantipyrine mutant neuron loss novel therapeutics oxidation receptor receptor binding research study spreading depression

项目摘要

DESCRIPTION (provided by applicant): Cyclooxygenase, the enzyme that catalyzes the production of prostaglandins from arachidonic acid, has long been thought to play a role in exacerbating injury due to cerebral ischemia via its vascular and inflammatory effects. Recently it has been found that the inducible isoform of the enzyme, cyclooxygenase 2 (COX2), is expressed in high levels within neurons. We hypothesize that COX2 activity within the neuron itself promotes cell death after hypoxia/ischemia. The proposed experiments are designed to test whether COX2 activity exacerbates anoxic injury by oxidative stress, production of prostaglandins including the cyclopentenone prostaglandins, or both. The following specific aims are proposed: 1. Test whether COX2 activity exacerbates anoxic injury through production of oxidative stress via peroxidase activity. 2. Test whether COX2 activity exacerbates anoxic injury through production of prostaglandins via cyclooxygenase activity. 3. Test whether 15-deoxy-delta(12,14) -PGJ2 or other prostaglandins activate PPARgamma receptor binding and exacerbate anoxic neuronal death via activation of the PPARgamma receptor. COX2 activity has been implicated in the pathogenesis of stroke and neurodegenerative diseases, including Atzheimer's disease and amyotrophic lateral sclerosis. The current studies will address the mechanisms by which COX2 activity can directly injure neurons and thus could lead to new therapeutic strategies for stroke and neurodegenerative diseases.

描述（由申请人提供）：环加氧酶是一种催化花生四烯酸产生前列腺素的酶，长期以来一直被认为通过其血管和炎症作用在加剧脑缺血损伤中发挥作用。最近发现，该酶的诱导型亚型环氧合酶 2 (COX2) 在神经元内高水平表达。我们假设神经元本身内的 COX2 活性在缺氧/缺血后促进细胞死亡。所提出的实验旨在测试 COX2 活性是否会因氧化应激、前列腺素（包括环戊烯酮前列腺素）的产生或两者而加剧缺氧损伤。提出以下具体目标： 1.测试COX2活性是否通过过氧化物酶活性产生氧化应激而加剧缺氧损伤。 2.测试COX2活性是否通过环氧合酶活性产生前列腺素而加剧缺氧损伤。 3.测试15-脱氧-δ(12,14)-PGJ2或其他前列腺素是否激活PPARγ受体结合并通过激活PPARγ受体加剧缺氧性神经元死亡。 COX2 活性与中风和神经退行性疾病（包括阿茨海默氏病和肌萎缩侧索硬化症）的发病机制有关。目前的研究将探讨 COX2 活性直接损伤神经元的机制，从而可能为中风和神经退行性疾病带来新的治疗策略。