Mechanisms of host-bacterial interactions, ileitis and granuloma formation in Agr

描述(申请人提供)：炎症性肠病(IBD)的特征是慢性、复发性肠道炎症，导致腹泻、腹痛和营养不良等虚弱症状。它的主要形式是克罗恩病和溃疡性结肠炎。克罗恩病的特点是穿壁性肠炎伴肉芽肿形成。先天性免疫缺陷、自噬、内质网应激和肠道菌群异常都是克罗恩病的致病因素。内质网应激诱导自噬，损害对病原菌的杀灭。错误折叠的质膜和分泌的蛋白质会导致内质网应激。蛋白质二硫键异构酶修复错误折叠的蛋白质，减少内质网应激。前梯度2(AGR2)是一种表达于肠道分泌细胞和巨噬细胞的蛋白二硫键异构酶。人类AGR2基因变种降低其表达与IBD风险增加相关。为了了解AGR2在IBD中的作用，我们培育了AGR2生殖系和条件性基因敲除小鼠。这些农业/小鼠模型出现戏剧性回肠炎、结肠炎、多核巨细胞和肉芽肿，这是克罗恩病患者的特征，以前从未在任何人类IBD风险基因的小鼠模型中观察到。肠杯、潘氏细胞和巨噬细胞增加了内质网应激。P62和LC3-II是必需的自噬基因，随着AGR2基因的敲除而积累。重要的是，我们已经从农业回肠微生物群中培养出粘附性和侵袭性大肠杆菌(我们和其他人在克罗恩病患者的回肠中发现了这种细菌)。这个项目的总体目标是了解农业2/-肠道上皮细胞、巨噬细胞和异常宿主微生物群相互作用导致多核巨细胞、肉芽肿、回肠炎和结肠炎的机制。

DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) is characterized by chronic, relapsing intestinal inflammation producing debilitating symptoms of diarrhea, abdominal pain and malnutrition. Its main forms are Crohn's disease and ulcerative colitis. Crohn's disease is characterized by transmural intestinal inflammation with granuloma formation. Defects in innate immunity, autophagy, endoplasmic reticulum (ER) stress and abnormal enteric microflora all contribute to Crohn's disease. Endoplasmic reticulum stress induces autophagy and impairs killing of pathogenic bacteria. The presence of misfolded plasma membrane and secreted proteins causes ER stress. Protein disulfide isomerases repair misfolded proteins and reduce ER stress. Anterior Gradient 2 (AGR2) is a protein disulfide isomerase expressed in intestinal secretory cells and macrophages. Human AGR2 genetic variants that decrease its expression are associated with increased IBD risk. To understand the role of AGR2 in IBD we generated Agr2 germline and conditional knockout mice. These Agr2-/- mouse models develop dramatic ileitis, colitis, multinucleated giant cells and granulomas, a characteristic Crohn's disease patient feature that has not been previously observed in any mouse model of a human IBD risk gene. Intestinal goblet, Paneth cells and macrophages have increased ER stress. p62 and LC3-II, essential autophagy genes, accumulate with AGR2 knockdown. Importantly, we have cultured mucosally adherent and invasive E. coli (which we and others have found in the ileum of Crohn's patients) from Agr2-/- ileal microflora. The overall goal of this project is to understand the mechanism of Agr2-/- intestinal epithelia, macrophage and abnormal host microflora interaction to cause multinucleate giant cells, granulomas, ileitis and colitis.