NITROXIDE THERAPY FOR INFLAMMATORY BOWEL DISEASE

描述（改编自应用程序）：自由基发挥重要作用 在炎症性肠病（IBD）中， 这些氧化剂的副作用可以提供新的治疗方法。抗氧化 据报道可减少结肠炎模型中的组织损伤，但更有效， 需要稳定和生物可利用的抗氧化剂化合物。该项目将 测试基于多硝酰化技术的新型抗氧化剂，或 氮氧自由基（稳定的N-氧自由基）与生物大分子的连接。在 初步研究表明，多硝基淀粉（PNS）与 游离（未结合的）氮氧化合物Tempol，以减少氧化剂（特别是 超氧化物）和减轻TNBS诱导小鼠结肠炎中的炎症。我们 假设TNBS结肠炎涉及显著的超氧化物介导的损伤， PNS和Tempol可以减轻这种损伤。具体目标是：（1） 生产PNS并表征其抗氧化活性。(2)药代 确定最佳剂量和给药途径。(3)定义疗效 TNBS诱导的小鼠结肠炎。如果成功，第二阶段将确定 IBD动物模型中的作用机制（包括IL-10-/-敲除 小鼠自发发展结肠炎）和其他研究所需的 IBD临床试验进展。 拟定商业应用： 炎症性肠病是一个重要的健康问题。 如果这项研究成功， 导致用于治疗IBD的新型治疗剂的开发。 这将 代表了重要的商业机会并为患者提供了实质性的益处。

DESCRIPTION (Adapted from the application): Free radicals play important roles in inflammatory bowel disease (IBD), and the reduction or elimination of the adverse effects of these oxidants could provide novel therapies. Antioxidants have been reported to reduce tissue injury in colitis models, but more potent, stable and bioavailable antioxidant compounds are required. This project will test a new class ofantioxidants based on polynitroxylation technology, or linkage of nitroxides (stable N-oxyl radicals) to biological macromolecules. In a preliminary study, polynitroxyl-starch (PNS) acted synergistically with the free (unbound) nitroxide compound Tempol to reduce oxidants (especially superoxide) and attenuate inflammation in TNBS-induced murine colitis. We hypothesize that TNBS colitis involves significant superoxide-mediated injury, and that PNS and Tempol can attenuate this injury. Specific aims are: (1) Produce PNS and characterize its antioxidant activity. (2) Pharmacokinetically define optimal dose and route of administration. (3) Define efficacy in TNBS-induced mouse colitis. If this is successful, Phase II will define mechanisms of action in animal models of IBD (including the IL-10-/- knockout mouse which spontaneously develops colitis) and other studies required for progression to clinical testing in IBD. PROPOSED COMMERCIAL APPLICATION: Inflammatory bowel disease is a significant health problem. If successful this research will lead to the development of a novel therapeutic agent(s) for the treatment of IBD. This would represent a significant commercial opportunity and provide substantial benefit to patients.