Altering XOR Product Identity to Treat Ischemic Stroke

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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.