Innate Immunity End Experimental Crohn's Disease

描述（由申请人提供）：克罗恩病（CD）是一种使人衰弱的疾病，目前尚无治愈方法。乳糜泻的确切病因尚不清楚。越来越多的证据表明，乳糜泻可能是由遗传易感宿主对“未知”抗原的先天免疫反应失调引起的。本项目申请的中心假设是CD是由先天性免疫对腔内抗原的异常反应引起的。我们的初步数据表明，nod2信号和肠通透性的失调可能先于慢性回肠炎的发展。这些影响与异常的树突状和巨噬细胞功能以及适应性免疫系统的过度激活有关。由此产生的促炎作用导致了乳糜泻的慢性炎症反应特征。本项目的总体目标是了解先天性免疫功能障碍在乳糜泻发病机制中的作用，最终目标是为这种毁灭性疾病开发新的治疗策略。该项目将由Pablo cominell博士指导，包括4个项目和2个核心。由Fabio Cominelli博士领导的项目1将验证nod2信号和MDP反应的缺陷是SAMP cd样回肠炎的原因。由Derek Abbott博士领导的项目2将专注于另一种假设，即nod2信号的夸大可能导致慢性肠道炎症。项目3由Klaus Ley博士领导，将研究骨髓细胞在慢性回肠炎中的作用。项目4由Theresa Pizarro博士领导，将研究上皮-免疫细胞的相互作用，特别是肠上皮、树突状细胞和T调节细胞之间的相互作用。这些计划由一个行政核心支持，它提供行政支持并协调浓缩计划。小鼠/组织学中心将集中生产和繁殖实验性CD小鼠，并提供集中的病理和组织学分析。本项目的长期目标是了解实验性乳糜泻中先天免疫的关键致病机制，并可立即转化为人类疾病。

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.