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.

项目摘要 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是 目前大于34％的人口。与肥胖相关的关键合并症是中风的 据报道，中央肥胖与缺血性事件的更大风险密切相关 而且结果更糟。中风最常见的临床治疗方法是给药 重组组织纤溶酶原激活剂（RTPA），该激活剂仅限于治疗窗口 中风后仅几个小时，确认迫切需要解决这个问题的方法 临床问题。通过认识到导致和 由中风事件导致的是肥胖，反应性物种产生的速度提高和 UA的血浆水平升高，我们建议针对这些组件的交点， 黄嘌呤氧化还原酶（XOR）。 XOR是一种在 肥胖是反应性物种的绝对来源，也是哺乳动物中UA的唯一来源。 提供的初步数据证明了鼠，饮食诱发的肥胖症会导致增强 循环XOR活性和UA水平，并揭示了一种新型的组织特异性鼠XOR 当肥胖时，敲除可以保持循环的XOR和UA的精益水平。重要的是，我们 展示了XOR依赖性的，亚硝酸盐介导的氧化应激和UA水平的降低 啮齿动物大脑。此外，这些数据得到了肥胖鼠组织的离体分析的支持 •XOR和亚硝酸盐催化的任何生成的速率很高。总体而言，这些 调查结果支持我们的总体假设，即将XOR活性转化为 炎症产物（氧化剂和UA）至不会改善缺血性卒中结果 肥胖。以下目的将检验以下假设：1）确定 肥胖小鼠中XOR衍生的ROS与UA的缺血性中风，2）利用肥胖症 - XOR的相关升高以诱导XOR催化不会产生和改善中风 结果。在Toto中，该提案旨在利用与肥胖相关的XOR高程 通过将其产品身份从氧化剂切换到NO，从而改善了中风结果。