Role of Mammalian Chitinases in Inflammatory Bowel Disease

描述（由申请人提供）：炎症性肠病（IBD），包括溃疡性结肠炎（UC）和克罗恩病（CD），是一组影响个体终生的慢性炎症性疾病。一些研究表明，失调的宿主/肠道细菌相互作用是慢性肠道炎症发展所必需的。然而，强调初始宿主/微生物相互作用触发结肠炎和随后的结肠炎恶化步骤的确切机制尚未完全确定。我们最近发现了一种新的肠道炎症相关的诱导分子几丁质酶3样-1（CHI 3L 1），它由结肠上皮细胞（CEC）和固有层细胞产生。CHI 3L 1可能通过增强CEC上/中的细胞内细菌粘附和内化而参与结肠炎的发病机制。本研究的一个主要目标是确定CHI 3L 1在结肠炎发病机制中的生物学意义。在目的-I中，我们将通过施用特异性抗体在体内积极地研究CHI 3L 1在急性和慢性结肠炎的小鼠模型的发病机制中的体内生物学功能。在Aim-II中，我们将测试微生物衍生的几丁质结合蛋白和CEC衍生的CHI 3L 1在微生物对CEC的粘附和侵袭中的相互作用。在目标-III中，我们将定义口服给药的甲壳素（一种N-乙酰葡糖胺的聚合物和CHI 3L 1的底物）在急性和慢性结肠炎动物模型中的预防作用。这些研究将有助于阐明CHI 3L 1在炎症中的关键作用，并为开发新的基于抗CHI 3L 1的免疫治疗剂以及基于几丁质致敏的IBD预防方法提供理论基础。我们相信，从这项研究中获得的数据将提供一个重要的线索，了解CHI 3L 1在IBD的发病机制中的作用。公共卫生相关性：该提案的具体目的是确定几丁质酶3-like-1和几丁质在IBD发病机制中的生物学功能。这些研究将为在不久的将来开发人类IBD的治疗和预防方法提供重要信息。

DESCRIPTION (provided by applicant): Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are a group of chronic inflammatory disorders that affect individuals throughout life. Several studies have indicated that dysregulated host/enteric bacterial interactions are required for the development of chronic intestinal inflammation. However, the exact mechanisms underlining the initial host/microbial interaction in triggering colitis and the following steps for exacerbating colitis have not been fully defined. We have recently identified a novel, intestinal inflammation-associated inducible molecule Chitinase 3-like-1 (CHI3L1) that is produced by colonic epithelial cells (CECs) and lamina propria cells. CHI3L1 may be involved in the pathogenesis of colitis by enhancing intracellular bacterial adhesion and internalization on/into CECs. A major goal of this study is to define the biological significance of CHI3L1 in the pathogenesis of colitis. In Aim-I, we will examine the in vivo biological function of CHI3L1 in the pathogenesis of murine models of acute and chronic colitis actively in vivo through administration of the specific antibody. In Aim-II, we will test the interaction between microorganism-derived chitin-binding proteins and CEC-derived CHI3L1 in the adhesion and invasion of microorganisms to CECs. In Aim-III, we will define a prophylactic effect of orally administered chitin, a polymer of N-acetylglucosamine and substrate for CHI3L1, in animal models of acute and chronic colitis. These studies will help clarify the critical role of CHI3L1 in inflammation and provide a rationale for the development of novel anti- CHI3L1 based immuno-therapeutics, as well as chitin sensitization-based prophylactic approaches in IBD. We believe that the data obtained from this study would provide an important clue for understanding the role of CHI3L1 in the pathogenesis of IBD. PUBLIC HEALTH RELEVANCE: The specific aims of this proposal are designed to define the biological function of chitinase 3-like-1 and chitin in the pathogenesis of IBD. These studies will provide important information for developing therapeutic and prophylactic approaches in human IBD in the near future.