Dietary anti-inflammatory chitin in colitis

描述（由申请人提供）：炎症性肠病（IBD）是一种慢性复发性结肠炎，与梗阻、瘘管和结直肠癌风险相关。它可能是由免疫失调的宿主和微生物相互作用引起的。有效的抗炎药物与毒性相关，因此需要新的IBD治疗策略。饮食葡萄糖胺，广泛用于关节炎，心血管疾病和癌症预防，建议作为IBD的治疗。我们和其他人已经表明，小鼠结肠炎症被口服甲壳素（一种天然葡萄糖胺聚合物衍生物）抑制。疗效取决于具体形式的甲壳素，可作为可溶性甲壳素，甲壳素微粒在1 - 10？m（CMPs），大甲壳素珠在40 - 100？m（LCBs），壳聚糖微粒在1 - 10？m（CsMPs）和可溶性壳聚糖。我们建议确定哪种甲壳素制剂在抑制结肠炎活动方面是最有效的。口服甲壳素可通过其甲壳素结合蛋白（CBP）（包括Toll样受体2（TLR 2）和CD 44）诱导肠上皮细胞和/或结肠巨噬细胞的反应。这两种CBP是几丁质治疗的合理靶点，因为已知它们在小鼠结肠炎中具有抗炎和促炎作用，并且似乎在功能上相互下调。基于我们的初步结果，我们假设最佳的抗结肠炎作用的甲壳素制剂将上调TLR 2和下调CD 44活性，并保护肠上皮细胞。为了验证这一假设，我们将确定几丁质形式，改善感染柠檬酸杆菌啮齿动物的结肠炎作为由肠致病性大肠杆菌引起的人类IBD的模型。我们将测量结肠上皮细胞和结肠巨噬细胞中的TLR 2和CD 44水平，以评估这些CBP活性是否与正常肠道微生物群的变化相关。接下来，使用缺乏TLR 2和CD 44的小鼠，我们将确定TLR 2和CD 44是否负责通过上述选择的最佳几丁质形式改善结肠炎。从这项工作中获得的知识将适用于建立明确的抗结肠炎治疗方案，转化为IBD的临床研究，并可能扩展到其他疾病，其中CBP被预测发挥关键的炎症作用。此外，它将使研究生和本科生参与临床相关的免疫学研究，鼓励他们的科学发展，并使他们对补充和替代药物有更深入的了解。

DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) is a chronic relapsing colitis, associated with risk for obstruction, fistula and colorectal cancer. It is probaly caused by immunologically dysregulated host and microbial interactions. Effective anti-inflammatory medications are associated with toxicities, so new treatment strategies for IBD are needed. Dietary glucosamine, widely used for arthritis, cardiovascular disease, and cancer prevention, is suggested as a therapy for IBD. We and others have shown that colonic inflammation in mice is suppressed by oral administration of chitin, a natural glucosamine polymer derivative. The efficacy depends on the specific form of chitin, available as soluble chitin, chitin microparticles at 1 - 10 ?m (CMPs), large chitin beads at 40 - 100 ?m (LCBs), chitosan microparticles at 1 - 10 ?m (CsMPs) and soluble chitosan. We propose to determine which chitin preparation is the most effective in suppressing colitis activities. Oral chitin may induce responses by intestinal epithelial cells and/or colonic macrophages through their chitin binding proteins (CBPs), including toll-like receptor 2 (TLR2) and CD44. These two CBPs are reasonable targets for chitin treatment since they are known to be anti- and pro-inflammatory in mouse colitis, and seem to functionally down-regulate each other. Based on our preliminary results, we hypothesize that chitin preparations optimal for anti-colitis effects will up-regulate TLR2 and down-regulate CD44 activities, and protect intestinal epithelia. To test the hypothesis, we will determine the chitin form(s) that ameliorate colitis in mice infected with Citrobacter rodentium as a model of human IBD caused by enteropathogenic Escherichia coli. We will measure TLR2 and CD44 levels in the colon epithelial cells and colon macrophages to assess whether these CBP activities are associated with a shift in normal gut microbiota. Next, using mice deficient of TLR2 and CD44, we will determine whether TLR2 and CD44 are responsible for amelioration of colitis by the optimal chitin form selected above. The knowledge gained from this work will apply to the establishment of defined anti-colitis therapeutic protocol translating o clinical studies of IBD and possibly extended to other diseases where CBPs have been predicted to play key inflammatory roles. Furthermore, it will engage graduate and undergraduate students in clinically-relevant immunology research, encouraging their scientific development and giving them a deeper appreciation of complementary and alternative medicines.