Host-bacterial interactions, ileitis and granuloma formation in Agr2-/- mice

Agr2-/- 小鼠中宿主-细菌相互作用、回肠炎和肉芽肿形成

• 批准号: 8246773
• 负责人: Steven M Lipkin
• 金额: $ 38.88万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-15 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8246773
• 关键词: Abdominal Pain; Abnormal Macrophage; Anterior; Autophagocytosis; Autophagosome; Bacteria; Canis familiaris; Cell membrane; Cells; Characteristics; Chronic; Colitis; Colon; Crohn' s disease; Crohn' s disease of the ileum; Data; Defect; Diarrhea; Drug Delivery Systems; Endoplasmic Reticulum; Enteral; Environmental Risk Factor; Escherichia coli; Gene Mutation; Genes; Genetic; Germ-Free; Giant Cell Granuloma; Giant Cells; Goals; Granuloma; Granulomatous; House mice; Housing; Human; Ileitis; Inflammation; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Interleukin-10; Intestines; Knock-out; Knockout Mice; Malnutrition; Modeling; Mono-S; Mus; Natural Immunity; Paneth Cells; Pathway interactions; Patients; Phagocytosis; Prevention therapy; Process; Production; Protein Disulfide Isomerase; Proteins; Relapse; Reporter; Role; Secretory Cell; Signal Pathway; Signal Transduction; Small Interfering RNA; Sterility; Symptoms; TNF gene; Testing; Transgenic Organisms; Ulcerative Colitis; Viral; biological adaptation to stress; disorder risk; endoplasmic reticulum stress; genetic variant; ileum; improved; in vivo; insight; intestinal epithelium; killings; large bowel Crohn' s disease; macrophage; mouse model; novel; pathogenic bacteria; protein degradation; protein misfolding; repaired; research study; response

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. PUBLIC HEALTH RELEVANCE: Our study will provide novel insights important to understand the mechanistic roles of AGR2. Our long term goal is to identify new signaling pathways and drug targets to improve upon current IBD exacerbation prevention and therapy.

描述（由申请人提供）：炎症性肠病（IBD）的特征是慢性、复发性肠道炎症，产生腹泻、腹痛和营养不良等衰弱症状。其主要形式是克罗恩病和溃疡性结肠炎。克罗恩病的特征是具有肉芽肿形成的透壁肠道炎症。先天免疫、自噬、内质网 (ER) 应激和肠道微生物群异常等缺陷都会导致克罗恩病。内质网应激会诱导自噬并损害对病原菌的杀灭。错误折叠的质膜和分泌蛋白的存在会导致内质网应激。蛋白质二硫键异构酶修复错误折叠的蛋白质并减少内质网应激。 Anterior Gradient 2 (AGR2) 是一种在肠道分泌细胞和巨噬细胞中表达的蛋白质二硫键异构酶。降低其表达的人类 AGR2 基因变异与 IBD 风险增加相关。为了了解 AGR2 在 IBD 中的作用，我们培育了 Agr2 种系小鼠和条件敲除小鼠。这些 Agr2-/- 小鼠模型会出现严重的回肠炎、结肠炎、多核巨细胞和肉芽肿，这是克罗恩病患者的一个特征，此前在任何人类 IBD 风险基因的小鼠模型中都没有观察到过。肠杯、潘氏细胞和巨噬细胞增加了内质网应激。 p62 和 LC3-II 是重要的自噬基因，随着 AGR2 敲低而积累。重要的是，我们从 Agr2-/- 回肠微生物群中培养了粘膜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大肠杆菌）。该项目的总体目标是了解Agr2-/-肠上皮、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。 公共健康相关性：我们的研究将为理解 AGR2 的机制作用提供重要的新颖见解。我们的长期目标是确定新的信号通路和药物靶点，以改善当前 IBD 恶化的预防和治疗。