NOD-like Receptors in Intestinal Inflammation

摘要 先天免疫受体的发现彻底改变了先天免疫领域。一个意想不到 发现先天性免疫受体不仅位于细胞膜上，而且大多数都位于细胞膜上。 发现于细胞内。这使得细胞能够检测来自病原体相关分子的细胞内扰动， PAMP模式或损伤相关分子模式（DAMP）。我们的研究显示， 细胞内先天免疫受体在减轻炎症和塑造微生物组中的新作用 炎症性肠病（IBD）。中心假设是，抑制的双向相互作用 细胞内先天受体与微生物组的结合是IBD的主要促成因素。我们的建议重点是 细胞内NLR（核苷酸结合结构域，富含亮氨酸重复序列的蛋白质，或NOD样受体） proteins.虽然NOD2在克罗恩病中仍然是最突出的，但我们已经关注了其他基因的作用。 结肠炎中的NLR。我们有数据表明，几种抑制性NLR蛋白强烈地减轻了肠道 通过减少免疫信号传导途径的激活从而防止炎性细胞因子 这是结肠炎不可或缺的反应。这反过来又会影响先天性和适应性免疫细胞，以及 结肠上皮细胞我们还表明，这些抑制性NLR影响微生物组，部分是通过 保持细菌可以包含促炎反应。因此，第一个目标是了解 抑制性NLR和肠道微生物群的双向相互作用通过减轻小鼠肠道炎症 与项目2、4和动物模型核心A一起工作。另一个过度的目标是评估 在小鼠中获得的结果与人类的翻译相关性。与Project 3和人体组织合作 和基因组学核心B，我们将分析患者来源的材料，以验证我们在小鼠中发现的意义 炎症性肠病患者的样本。

ABSTRACT The discovery of innate immune receptors has revolutionized the field of innate immunity. An unexpected finding is that innate immune receptor are not only located on the cell membrane, but a majority of these are found intracellularly. This allows cells to detect intracellular perturbation from pathogen-associated molecular patterns (PAMPs) or from damage-associated molecular patterns (DAMPs). Our studies have revealed a novel roles of intracellular innate immune receptor in attenuating inflammation and shaping the microbiome during inflammatory bowel disease (IBD). The central hypothesis is that the bi-directional interplay of inhibitory intracellular innate receptors with the microbiome is a major contributing factor in IBD. Our proposal focuses on the intracellular NLR (nucleotide-binding domain, leucine-rich repeat containing protein, or NOD-like receptor) proteins. While NOD2 remains the most prominent in Crohns’ disease, we have focused on the role of other NLRs in colitis. We have data to show that several inhibitory NLR proteins strongly mitigate intestinal inflammation by reducing the activation of immune signaling pathway thus preventing an inflammatory cytokine response that is integral to colitis. This in turn can affect both innate and adaptive immune cells, as well as colon epithelial cells. We have also shown that these inhibitory NLRs affect the microbiome, partly by maintaining bacteria that can contain a pro-inflammatory response. Thus the first goal is to understand the bidirectional interaction of inhibitory NLR and the gut microbiota in mitigating gut inflammation in mice by working with Projects 2, 4 and the Animal Models Core A. Another over-arching goal is to assess the translational relevance of results obtained in mice to humans. Working with Project 3 and the Human Tissue and Genomics Core B, we will analyze patient-derived material to verify the significance of our findings in mice to inflammatory bowel disease patient samples.