Innate Immunity End Experimental Crohn's Disease

先天免疫结束实验性克罗恩病

基本信息

批准号：
9132952
负责人：
Fabio Cominelli
金额：
$ 10万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9132952
关键词：
A Mouse AKR/J Mouse Affect Age Antigens Architecture Area Autoimmune Process B-Lymphocytes Bacteria Breeding Brothers Cell Communication Cells Characteristics Chronic Chronic Inflammatory Infiltrate Collagen Colorado Crohn&apos s disease Data Defect Dendritic Cells Deposition Development Disease Distal part of ileum Environmental Risk Factor Epithelial Equilibrium Etiology Exhibits Experimental Models Fistula Gastroenterology Generations Genes Genetic Genetic Predisposition to Disease Goals Granulomatous Head Histology Homeostasis Human Hyperplasia Hypersensitivity Hypertrophy IL8 gene Ileitis Immune Immune System Diseases Immune response Immune system Immunologic Factors Immunology Individual Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inflammatory disease of the intestine Institutes Institution Interferon Type II Interleukin-1 Intestinal Mucosa Intestines Japan Laboratories Lead Learning Leukocytes Longevity Lymphocyte Mediating Modeling Mouse Strains Mucins Mucous Membrane Mus Muscle Mutation Myeloid Cells NF-kappa B Natural Immunity Neutrophil Infiltration Organ P-selectin ligand protein Partner in relationship Pathogenesis Pathologic Pathology Patients Pattern recognition receptor Peptidoglycan Permeability Phenotype Play Population Principal Investigator Probiotics Production Proteins Publications Regulatory T-Lymphocyte Relapse Research Research Personnel Role Signal Transduction Sister Societies Source Susceptibility Gene Sweden System TNF gene Terminal Ileitis Testing Therapeutic Tokyo Translating Ulcerative Colitis Universities University Hospitals Work activating transcription factor adaptive immunity base clinical application clinical phenotype cost cytokine enteritis human disease improved interest intestinal epithelium macrophage mouse model novel therapeutics premature prevent programs relating to nervous system response restoration senescence skin lesion theories

项目摘要

DESCRIPTION (provided by applicant): Crohn's disease (CD) is a debilitating condition with no known cure. The precise cause(s) of CD remain undefined. Increasing evidence suggests that CD may be initiated by a dysregulated innate immune response against "unknown" antigens in a genetically-susceptible host. The central hypothesis of this Program Project application is that CD results from a abnormality in Innate immune responses to luminal antigens. Our preliminary data suggests that a dysregulation in N0D2 signaling and intestinal permeability may precede the development of chronic ileitis. These effects are associated with abnormal dendritic and macrophage function and excessive activation of the adaptive immune system. The resulting proinflammatory effects leads to the chronic inflammatory response characteristic of CD. The overall objective of this Program Project is to understand the mechanisms of innate immune dysfunction in CD pathogenesis, with the ultimate goal of developing new therapeutic strategies for this devastating disease. The Program Project will be directed by Dr. Pablo Cominelll and will consist of 4 projects and 2 cores. Project 1, headed by Dr. Fabio Cominelli, will test the hypothesis that a deficit in N0D2 signaling and MDP responses is responsible for SAMP CD-like ileitis. Project 2, headed by Dr. Derek Abbott, will focus on the alternative hypothesis that an exaggeration in N0D2 signaling may result in chronic intestinal inflammation. Project 3, headed by Dr. Klaus Ley, will investigate the role of myeloid cells in mediating chronic ileitis. Project 4, headed by Dr. Theresa Pizarro, will study epithelial-immune cell interactions, specifically the interplay between the intestinal epithelium, dendritic cells, and T regulatory cells. These projects are supported by an Administrative Core, which provides administrative support and coordinates the enrichment program. A Mouse/Histology Core will centralize the production and breeding of mice with experimental CD and provide centralized pathologic and histological analysis. The long-term goal of this Program Project is to understand key pathogenic mechanisms of innate immunity in experimental CD, which can be immediately translated to the human condition.

描述（由申请人提供）：克罗恩病（CD）是一种衰弱的状况，没有已知的治愈方法。 CD的确切原因仍然不确定。越来越多的证据表明，CD可能是通过对遗传敏感宿主中“未知”抗原的先天免疫反应引发的。该计划项目应用的中心假设是CD是由对腔抗原的先天免疫反应异常引起的。我们的初步数据表明，N0D2信号传导和肠道通透性的失调可能在慢性回肠炎的发展之前。这些作用与树突状异常和巨噬细胞功能以及适应性免疫系统的过度激活有关。产生的促炎作用导致CD的慢性炎症反应特征。该计划项目的总体目标是了解CD发病机理中先天免疫功能障碍的机制，其最终目的是为这种毁灭性疾病开发新的治疗策略。该计划项目将由Pablo Cominelll博士执导，将由4个项目和2个核心组成。由Fabio Cominelli博士领导的项目1将检验以下假设：N0D2信号传导和MDP反应的赤字是导致SAMP CD类状肠炎的原因。由德里克·雅培（Derek Abbott）博士领导的项目2将集中在替代假设上，即N0D2信号传导的夸张可能导致慢性肠炎。由克劳斯·莱伊（Klaus Ley）博士领导的项目3将研究髓样细胞在介导慢性回肠炎中的作用。由Theresa Pizarro博士领导的项目4将研究上皮免疫细胞相互作用，特别是肠上皮，树突状细胞和T调节细胞之间的相互作用。这些项目得到了行政核心的支持，该核心提供行政支持并协调丰富计划。小鼠/组织学核心将通过实验CD集中小鼠的产生和繁殖，并提供集中的病理和组织学分析。该计划项目的长期目标是了解实验CD中先天免疫的关键致病机制，可以立即将其转化为人类状况。