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

描述（由申请人提供）：在存在大量肠道微生物的情况下，肠道中的先天性和获得性免疫应答必须促进体内平衡，同时保持保护身体免受侵入性病原体侵害的能力。成年人的肠道中居住着100万亿个微生物，是整个人体细胞数量的10倍。共生细菌为宿主提供多种益处，包括处理必需营养素、调节能量平衡、保护免受病原体侵害和维持上皮完整性。然而，对结肠细菌的不适当的免疫反应可能导致慢性炎症性肠病和危及生命的结肠炎。宿主细胞通过模式识别分子识别微生物，包括Toll样受体（TLR），其结合微生物细胞壁成分，核酸和其他副产物。MyD 88是一种细胞质衔接蛋白，其转导从大多数TLR以及IL-1 R家族成员发出的信号。最近的研究表明，MyD 88表达遗传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-1 R信号传导在肠道炎症调节中的关键作用。我们的初步数据表明，MyD 88缺陷型小鼠严重抑制了多聚免疫球蛋白受体（plgR）的表达，plgR是介导保护性伊加抗体上皮转运的关键抗炎分子。其他人最近的工作表明，plgR缺陷小鼠与MyD 88缺陷小鼠一样，对化学诱导的结肠炎特别敏感。这项研究的目的是检验上皮细胞表达MyD 88对于调节plgR基因表达和保护实验性结肠炎至关重要的假设。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性MyD 88信号传导。首先，我们将分析这些小鼠对实验性结肠炎的易感性。其次，我们将分析结肠中促炎和抗炎基因表达的模式。这些实验应该增加我们对上皮特异性MyD 88信号传导以及上皮细胞和免疫细胞之间的串扰的了解，这是识别对结肠细菌的正常和失调反应的关键。

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.