Altering XOR Product Identity to Treat Ischemic Stroke

改变 XOR 产品特性来治疗缺血性中风

• 批准号: 10025935
• 负责人: Eric Eugene Kelley
• 金额: $ 26.3万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-08 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10025935
• 关键词: Address; Adjuvant; Allopurinol; Alteplase; Brain; Cardiovascular Diseases; Centers of Research Excellence; Clinical; Clinical Treatment; Cysteine; Data; Dependence; Diet; Elements; Endothelium; Enzymes; Event; Flavins; Free Radicals; Generations; Genes; Genetic Models; Healthcare; Hour; Human; Hydrogen Peroxide; Hypoxanthines; Hypoxia; Infarction; Inflammatory; Ischemia; Ischemic Stroke; Knock-out; Link; Liver; Mammals; Mediating; Microglia; Modeling; Mus; NADH; Nervous System Physiology; Neurologic Deficit; Nitrites; Obese Mice; Obesity; Outcome; Oxidants; Oxidases; Oxidative Stress; Oxides; Oxidoreductase; Pathogenicity; Plasma; Population; Process; Proteolysis; Reperfusion Therapy; Reporting; Resistance; Risk; Risk Factors; Rodent; Source; Stroke; Testing; Therapeutic; Thinness; Tissues; Universities; Uric Acid; Vascular Endothelium; West Virginia; XDH gene; Xanthines; base; comorbidity; design; improved; improved outcome; in vivo; molybdenum cofactor; novel; novel strategies; oxidation; oxidoreductase inhibitor; post stroke; prevent; stroke event; stroke outcome; stroke risk; stroke therapy; success

Project Summary Obesity is an imminent healthcare crisis in West Virginia as the number of obese citizens is currently greater than 34% of the population. A crucial comorbidity allied to obesity is stroke as central adiposity is reported to be strongly associated with greater risk for an ischemic event and worse outcomes. The most common clinical treatment for stroke is administration of recombinant tissue plasminogen activators (rtPAs) which is limited to a therapeutic window of only a few hours post stroke affirming the urgent need for novel approaches to address this clinical issue. By recognizing that key elements of the pathogenic processes leading to and resulting from a stroke event are obesity, enhanced rates of reactive species generation and elevated plasma levels of UA, we propose to target the intersection of these components, xanthine oxidoreductase (XOR). XOR is a molybdopterin/flavin enzyme that is up-regulated in obesity, is an abundant source of reactive species and the sole source of UA in mammals. We provide preliminary data that demonstrates murine, diet-induced obesity results in enhanced circulating XOR activity and UA levels and reveal that a novel tissue-specific, murine XOR knockout maintains lean levels of circulating XOR and UA when obese. Importantly, we demonstrate a XOR-dependent, nitrite-mediated, reduction in oxidative stress and UA levels in rodent brain. Furthermore, these data are supported by ex vivo analysis of obese murine tissues where significant rates of NO generation are catalyzed by XOR and nitrite. In aggregate, these findings support our overarching hypothesis that diverting XOR activity from pro- inflammatory products (oxidants and UA) to NO will improve ischemic stroke outcomes in obesity. The following Aims will test this hypothesis: 1) Determine the relative impact of XOR-derived ROS versus UA on ischemic stroke in obese mice and 2) Utilize obesity- associated elevation of XOR to induce XOR-catalyzed NO generation and improve stroke outcome.In toto, this proposal is designed to capitalize on obesity-associated elevation in XOR by switching its product identity from oxidants to NO and thus improve stroke outcome.

项目概要 肥胖是西弗吉尼亚州迫在眉睫的医疗危机，因为肥胖公民的数量 目前，超过 34% 的人口患有与肥胖相关的一个重要合并症，即中风。 据报道，中心性肥胖与缺血事件的更大风险密切相关 中风最常见的临床治疗方法是服用药物。 重组组织纤溶酶原激活剂（rtPA），其治疗窗口仅限于 中风后仅几个小时，确认迫切需要新的方法来解决这一问题 通过认识导致和的致病过程的关键要素。 中风事件导致的结果是肥胖、活性物质生成率增加以及 血浆 UA 水平升高，我们建议针对这些成分的交叉点， 黄嘌呤氧化还原酶 (XOR) 是一种钼蝶呤/黄素酶，在体内表达上调。 肥胖是活性物质的丰富来源，也是哺乳动物中尿酸的唯一来源。 提供初步数据，证明小鼠饮食诱发的肥胖导致增强的 循环 XOR 活性和 UA 水平，揭示了一种新的组织特异性鼠 XOR 重要的是，在肥胖时，敲除可维持循环 XOR 和 UA 的瘦水平。 证明 XOR 依赖性、亚硝酸盐介导的氧化应激和 UA 水平降低 此外，这些数据得到了肥胖小鼠组织的离体分析的支持。 其中，XOR 和亚硝酸盐会催化产生大量 NO。 研究结果支持我们的总体假设，即异或活动从亲 炎症产物（氧化剂和 UA）转为 NO 将改善缺血性中风的结果 以下目标将检验这一假设：1) 确定肥胖的相对影响。 XOR 衍生的 ROS 与 UA 对肥胖小鼠缺血性中风的影响以及 2) 利用肥胖- XOR 的相关升高可诱导 XOR 催化的 NO 生成并改善中风 总的来说，该提案旨在利用 XOR 中与肥胖相关的升高 通过将其产品特性从氧化剂转变为一氧化氮，从而改善中风结果。