Role of Mammalian Chitinases in Inflammatory Bowel Disease

哺乳动物几丁质酶在炎症性肠病中的作用

基本信息

批准号：
8055050
负责人：
EMIKO MIZOGUCHI
金额：
$ 30.19万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8055050
关键词：
Acetylglucosamine Acute Adhesions Affect Affinity Animal Model Antibodies Bacteria Bacterial Adhesion Binding Binding Proteins Biological Biological Process Bone Marrow Transplantation CD40 Ligand Cell Adhesion Cells Chitin Chitinase Chronic Colitis Crohn&apos s disease Data Development Disease Dose Enteral Enterobacteriaceae Enterocolitis Epithelial Cells Escherichia coli Etiology Exposure to Future Goals Health Human Immune response Immunotherapeutic agent Individual Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inflammatory disease of the intestine Insecta Interleukin-1 Interleukin-10 Intestines Lamina Propria Lectin Life Lung Lymphocyte Mammals Mediating Modeling Mononuclear Mus Mutate Nematoda Oral Administration Pathogenesis Physiological Play Polymers Polysaccharides Regulation Research Role Structure T-Lymphocyte TNF gene Testing Therapeutic Ulcerative Colitis Up-Regulation base cytokine design in vivo microorganism microorganism interaction novel overexpression pathogenic bacteria prophylactic

项目摘要

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.

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。多项研究表明，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，引发结肠炎的最初宿主/微生物相互作用的确切机制以及加剧结肠炎的后续步骤尚未完全确定。我们最近发现了一种新型肠道炎症相关诱导分子几丁质酶 3-like-1 (CHI3L1)，它由结肠上皮细胞 (CEC) 和固有层细胞产生。 CHI3L1 可能通过增强细胞内细菌粘附和 CEC 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 CHI3L1 在结肠炎发病机制中的生物学意义。在 Aim-I 中，我们将通过施用特异性抗体，在体内主动检测 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在微生物对CEC的粘附和侵袭中的相互作用。在 Aim-III 中，我们将定义口服甲壳素（一种 N-乙酰氨基葡萄糖和 CHI3L1 底物的聚合物）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 CHI3L1 在炎症中的关键作用，并为开发基于抗 CHI3L1 的新型免疫疗法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。公共健康相关性：该提案的具体目标旨在明确几丁质酶 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。