Altering XOR Product Identity to Treat Ischemic Stroke

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 目前超过34%的人口。与肥胖相关的一种重要的合并症是中风， 据报道，中心性肥胖与缺血性事件的更大风险密切相关 更糟糕的结果。中风最常见的临床治疗是施用 重组组织纤溶酶原激活剂（rtPA），其限于以下治疗窗口： 中风后仅仅几个小时，就证实了迫切需要新的方法来解决这个问题。 临床问题。通过认识到导致和 中风事件导致肥胖、反应性物质生成速率增加， UA的血浆水平升高，我们建议靶向这些组分的交叉点， 黄嘌呤氧化还原酶（XOR）。XOR是一种在细胞中上调的异蝶呤/黄素酶， 肥胖是哺乳动物中反应性物质的丰富来源和UA的唯一来源。我们 提供了初步数据，证明小鼠，饮食诱导的肥胖导致增强 循环XOR活性和UA水平，并揭示了一种新的组织特异性，小鼠XOR 在肥胖时，敲除维持循环XOR和UA的瘦水平。重要的是我们 证明了XOR依赖性，亚硝酸盐介导的氧化应激和UA水平的降低， 啮齿动物的大脑此外，这些数据得到了肥胖小鼠组织的离体分析的支持 其中异或和亚硝酸盐催化显著速率的NO生成。总的来说，这些 研究结果支持了我们的总体假设，即将异或活动从亲核转移到非亲核， 炎症产物（氧化剂和UA）与一氧化氮的结合将改善缺血性卒中的结局 肥胖症。以下目标将检验这一假设：1）确定 肥胖小鼠缺血性中风中XOR衍生的ROS与UA的对比和2）利用肥胖- 相关的XOR升高，以诱导XOR催化的BNO生成并改善中风 结果。总的来说，这项建议旨在利用肥胖相关的海拔在异或 通过将其产品身份从氧化剂转换为NO，从而改善中风结果。

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.