The Role of 20-HETE in the Pathogenesis of Stroke

20-HETE 在中风发病机制中的作用

• 批准号: 7414556
• 负责人: SAMUEL M POLOYAC
• 金额: $ 28.57万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7414556
• 关键词: Acute; Analytical Chemistry; Animal Model; Arachidonic Acids; Attenuated; Blood Vessels; Blood flow; Brain; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Data; Future; Goals; Hydroxyeicosatetraenoic Acids; Infarction; Injury; Intervention; Ischemia; Ischemic Penumbra; Laboratories; Lesion; Mediating; Mediator of activation protein; Microsomes; Modality; Modeling; Molecular Biology; Mus; Neurons; Nitric Oxide; Outcome; Pathogenesis; Pathway interactions; Rattus; Regulation; Research; Research Personnel; Residual state; Resistance; Role; Severities; Soluble Guanylate Cyclase; Stroke; Techniques; Therapeutic; Time; Tissues; Transgenic Mice; Transgenic Organisms; base; cerebrovascular; human NOS3 protein; improved; in vivo; inhibitor/antagonist; ischemic lesion; mouse model; novel; programs; protective effect; therapeutic target

DESCRIPTION (provided by applicant): Decreasing tissue infarction in the ischemic penumbra is the primary therapeutic target after stroke. The degree of tissue damage in the ischemic penumbra is a function of the severity of the ischemic insult, which is a function of cerebral microvascular resistance. Recent studies have shown that the monohydroxylated metabolite of arachidonic acid, 20-hydroxyeicosatetraenoic acid (20-HETE), is an important regulator of cerebrovascular resistance and mediates the vascular effects of nitric oxide. Our laboratory has recently shown that inhibiting 20-HETE formation dramatically reduces lesion volume after temporary focal ischemia. Based on this data, we hypothesize that 20-HETE is an important contributor to ischemic damage via its vasoconstrictive effects on the cerebral microvasculature. The goals of this project are: 1) To determine the temporal relationship between 20-HETE formation, lesion volume, and outcome in the rat temporary focal ischemia model; 2) To identify the in vivo effect of 20-HETE alterations on cerebral blood flow after temporary focal ischemia; 3) To determine the role of 20-HETE on nitric oxide mediated protective effects after temporary focal ischemia. This project will utilize combinations of in vivo blood flow assessment, molecular biology, and analytical chemistry techniques in the rat and transgenic mouse models of temporary focal ischemia. The results of this research are necessary to determine: 1) The role of 20-HETE in the pathogenesis of stroke; 2) The effects of 20-HETE on cerebrovascular regulation during ischemia and during post-ischemic hypoperfusion after stroke; 3) The role of 20-HETE inhibition in mediating the neuroprotective effects of nitric oxide. Elucidation of these mechanisms will enable future studies to delineate the therapeutic utility of 20-HETE inhibitors as a mechanism to reduce tissue damage after stroke. Furthermore, these studies will provide important information about the role of monohydroxylated arachidonic acid metabolites as a contributing pathway in the pathogenesis of stroke.

描述（由申请人提供）：减少缺血性半衰期的组织梗塞是中风后的主要治疗靶标。缺血性半裸的组织损伤程度是缺血性损伤的严重程度的函数，这是脑微血管抗性的函数。最近的研究表明，花生四烯酸的单羟基化代谢产物，20-羟基乙酸苯甲酸（20-HETE）是脑血管耐药性的重要调节剂，并介导硝酸氧化物的血管效应。我们的实验室最近表明，抑制20-HeTe形成会大大减少暂时性局灶性缺血后的病变体积。基于这些数据，我们假设20-HETE是通过血管收缩对脑微脉管系统的血管收缩作用的重要原因。该项目的目标是：1）确定大鼠临时局灶性局灶性缺血模型中20-HETE形成，病变体积和结果之间的时间关系； 2）确定暂时性局灶性缺血后20-HETE改变对脑血流的体内影响； 3）确定20-HETE在临时局灶性缺血后一氧化氮介导的保护作用的作用。该项目将利用临时局部缺血的大鼠和转基因小鼠模型中体内血流评估，分子生物学和分析化学技术的组合。这项研究的结果对于确定：1）20-Hete在中风的发病机理中的作用； 2）20-HETE在缺血期间和中风后缺血后灌注期间对脑血管调节的影响； 3）20-HETE抑制在介导一氧化氮的神经保护作用中的作用。阐明这些机制将使未来的研究能够描述20-HETE抑制剂的治疗效用，以此作为减少中风后组织损伤的一种机制。此外，这些研究将提供有关单羟基化蛛网膜酸代谢产物作为中风发病机理的途径的重要信息。