Novel in vivo models for cell-type specific MyD88 signaling in the intestine

肠道细胞类型特异性 MyD88 信号传导的新型体内模型

• 批准号: 7497566
• 负责人: Charlotte S Kaetzel
• 金额: $ 21.56万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7497566
• 关键词: Adult; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Bacteria; Binding; Bone Marrow; Cell Wall; Cells; Chimera organism; Chronic; Colitis; Colon; Congenic Mice; Data; Depressed mood; Development; Epithelial; Epithelial Cells; Equilibrium; Experimental Models; Family; Gene Expression; Genus Cola; Goals; Homeostasis; Human; Immune; Immune response; Immunoglobulin A; Inflammation; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Interleukin-1; Intestines; Invasive; Knowledge; Lamina Propria; Lead; Life; Maintenance; Mediating; Microarray Analysis; Mononuclear; Mus; Nucleic Acids; Numbers; Nutrient; Oral Administration; Pattern; Pattern Recognition; Polymeric Immunoglobulin Receptors; Predisposition; Process; Proteins; Range; Regulation; Research; Role; Signal Transducing Adaptor Proteins; Signal Transduction; Sodium Dextran Sulfate; Testing; Time; Tissues; Toll-like receptors; Transgenes; Transgenic Mice; Transgenic Organisms; Wild Type Mouse; Work; cell type; commensal microbes; energy balance; in vivo Model; member; microbial; microorganism; mouse model; novel; pathogen; promoter; research study; response; selective expression

DESCRIPTION (provided by applicant): Innate and acquired immune responses in the intestine must promote homeostasis in the presence of large numbers of commensal microorganisms, while maintaining the capacity to defend the body against invasive pathogens. The adult human intestinal tract is inhabited by 100 trillion microorganisms, 10 times more than the number of human cells in the entire body. Commensal bacteria provide multiple benefits to the host, including processing of essential nutrients, regulation of energy balance, protection against pathogens and maintenance of epithelial integrity. However, inappropriate immune responses to colonic bacteria can lead to chronic inflammatory bowel disease and life-threatening colitis. Host cells recognize microorganisms through pattern recognition molecules including Toll-like receptors (TLRs), which bind microbial cell wall constituents, nucleic acids and other byproducts. MyD88 is a cytoplasmic adaptor protein that transduces signals emanating from most TLRs, as well as members of the IL-1R family. Recent studies have demonstrated that mice genetically deficient in MyD88 expression are more sensitive to experimental colitis than are wild-type mice, suggesting a key role for TLR and/or IL-1 R signaling in regulation of intestinal inflammation. Our preliminary data demonstrate that MyD88-deficient mice have severely depressed expression of the polymeric immunoglobulin receptor (plgR), a key anti-inflammatory molecule that mediates epithelial transport of protective IgA antibodies. Recent work by others has demonstrated that plgR-deficient mice are, like MyD88-deficient mice, particularly sensitive to chemically-induced colitis. The goal of the proposed research is to test the hypothesis that expression of MyD88 by epithelial cells is crucial for regulation of plgR gene expression and protection against experimental colitis. As a consequence of these studies we will generate novel chimeric and transgenic mouse models for studying epithelial-specific MyD88 signaling within the intact intestine. First, we will analyze the susceptibility of these mice to experimental colitis. Second, we will analyze patterns of pro- and anti-inflammatory gene expression in the colon. These experiments should increase our knowledge of epithelial-specific MyD88 signaling, as well as cross-talk between epithelial and immune cells, which is key to the identification of normal and dysregulated responses to colonic bacteria.

描述(申请人提供)：肠道内的先天性和获得性免疫反应必须在大量共生微生物存在的情况下促进体内平衡，同时保持防御身体免受侵袭性病原体侵袭的能力。成人肠道中栖息着100万亿个微生物，是整个人体细胞数量的10倍多。共生菌为寄主提供了多种益处，包括处理必需的营养物质、调节能量平衡、保护病原体和维持上皮完整性。然而，对结肠菌的不适当免疫反应可能会导致慢性炎症性肠病和危及生命的结肠炎。宿主细胞通过包括Toll样受体(TLRs)在内的模式识别分子识别微生物，TLRs结合微生物细胞壁成分、核酸和其他副产品。MyD88是一种细胞质接头蛋白，可传递来自大多数TLR以及IL-1R家族成员的信号。最近的研究表明，MyD88基因表达缺陷的小鼠比野生型小鼠对实验性结肠炎更敏感，这表明TLR和/或IL-1R信号在调节肠道炎症中发挥了关键作用。我们的初步数据表明，MyD88缺陷小鼠严重抑制了聚合免疫球蛋白受体(PlgR)的表达，plgR是一种关键的抗炎分子，介导保护性IgA抗体的上皮性运输。其他人最近的工作表明，plgR缺陷小鼠和MyD88缺陷小鼠一样，对化学诱导的结肠炎特别敏感。这项研究的目的是验证一种假设，即上皮细胞表达MyD88对于调节plgR基因表达和预防实验性结肠炎至关重要。作为这些研究的结果，我们将产生新的嵌合和转基因小鼠模型，用于研究完整肠道内上皮特异的MyD88信号。首先，我们将分析这些小鼠对实验性结肠炎的易感性。其次，我们将分析促炎和抗炎基因在结肠中的表达模式。这些实验应该增加我们对上皮特异性MyD88信号的了解，以及上皮细胞和免疫细胞之间的串扰，这是识别对结肠菌的正常和异常反应的关键。