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：
8244566
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/8244566
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），是一组慢性炎症性疾病，会影响一生。几项研究表明，慢性肠道炎症的发展需要失调的宿主/肠细菌相互作用。但是，在触发结肠炎中强调初始宿主/微生物相互作用的确切机制和加剧结肠炎的以下步骤尚未完全定义。我们最近确定了由结肠上皮细胞（CEC）和椎板prepria层产生的新型的，肠炎相关的诱导分子几片3型（CHI3L1）。 CHI3L1可能通过增强细胞内细菌粘附和内在化/进入CEC的内在化而参与结肠炎的发病机理。这项研究的主要目的是定义Chi3L1在结肠炎发病机理中的生物学意义。在AIM-I中，我们将检查CHI3L1在急性和慢性结肠炎的发病机理中通过施用特定抗体在体内主动的体内生物学功能。在AIM-II中，我们将测试微生物衍生的几丁质结合蛋白与CEC衍生的CHI3L1之间的相互作用，以在微生物对CEC的粘附和侵袭中。在AIM-III中，我们将在急性和慢性结肠炎的动物模型中定义口服甲壳质的预防作用，即甲壳质，N-乙酰葡萄糖的聚合物和CHI3L1的底物。这些研究将有助于阐明CHI3L1在炎症中的关键作用，并为开发新型抗CHI3L1的免疫治疗药以及IBD中基于几丁质敏化的预防性方法提供了理由。我们认为，从这项研究中获得的数据将为理解Chi3L1在IBD发病机理中的作用提供重要线索。公共卫生相关性：该提案的具体目的旨在定义几丁质酶3 like-1和几丁质在IBD发病机理中的生物学功能。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。