Role of Mammalian Chitinases in Inflammatory Bowel Disease

描述(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)，是一组影响个体一生的慢性炎症性疾病。一些研究表明，慢性肠炎的发生需要宿主/肠道细菌相互作用的失调。然而，引发结肠炎的最初宿主/微生物相互作用的确切机制以及加重结肠炎的以下步骤尚未完全确定。我们最近发现了一种新的肠道炎症相关诱导分子几丁质酶3-样-1(CHI3L1)，它由结肠上皮细胞(CECs)和固有层细胞产生。CHI3L1可能通过促进细菌在细胞内的黏附和内化而参与结肠炎的发病。本研究的一个主要目的是确定CHI3L1在结肠炎发病机制中的生物学意义。在AIM-I中，我们将通过注射特异性抗体，在体内主动检测CHI3L1在急、慢性结肠炎小鼠模型发病机制中的生物学作用。在AIM-II中，我们将测试微生物来源的几丁质结合蛋白和CEC来源的CHI3L1在微生物对CEC的黏附和入侵中的相互作用。在AIM-III中，我们将确定口服甲壳素对急性和慢性结肠炎动物模型的预防作用。甲壳素是N-乙酰氨基葡萄糖的聚合物，也是CHI3L1的底物。这些研究将有助于阐明CHI3L1在炎症中的关键作用，并为基于CHI3L1的新型免疫疗法的开发以及基于几丁质致敏的IBD预防方法的开发提供理论基础。我们相信，这项研究的数据将为理解CHI3L1在IBD发病机制中的作用提供重要线索。公共卫生相关性：这项提案的具体目的是为了确定几丁质酶3-样-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治疗和预防人类IBD的方法提供重要信息。

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.