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），是一组影响个体一生的慢性炎症性疾病。一些研究表明，宿主/肠道细菌相互作用失调是慢性肠道炎症发展所必需的。然而，引发结肠炎的宿主/微生物相互作用的确切机制以及导致结肠炎恶化的后续步骤尚未完全明确。我们最近发现了一种由结肠上皮细胞（CECs）和固有层细胞产生的新型肠炎症相关诱导分子几丁质酶3-like-1 （CHI3L1）。CHI3L1可能通过增强CECs细胞内细菌粘附和内化参与结肠炎的发病机制。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，我们将通过给药特异性抗体，在体内积极检测CHI3L1在急性和慢性结肠炎小鼠模型发病机制中的体内生物学功能。在Aim-II中，我们将测试微生物来源的几丁质结合蛋白和cec来源的CHI3L1在微生物粘附和侵袭cec中的相互作用。在Aim-III中，我们将确定口服几丁质（n -乙酰氨基葡萄糖和CHI3L1底物的聚合物）对急性和慢性结肠炎动物模型的预防作用。这些研究将有助于阐明CHI3L1在炎症中的关键作用，并为开发新的基于抗CHI3L1的免疫疗法以及基于几丁质致敏的IBD预防方法提供理论依据。我们相信本研究获得的数据将为理解CHI3L1在IBD发病机制中的作用提供重要线索。公共卫生相关性：本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。这些研究将在不久的将来为开发人类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.