SIGIRR-mediated Tumor Suppression

炎症性肠病（IBD）与结直肠癌风险升高相关。尽管 结肠粘膜与大量肠道细菌的持续接触，通常是低- 对这些潜在的促炎威胁做出反应。肠上皮层的功能不仅是 物理屏障，而且也是针对肠道细菌的先天性和适应性免疫屏障。长期 目的是了解TLR-IL-1 R信号传导如何介导细胞间的主动串扰， 和宿主以维持结肠上皮对肠道细菌的耐受性。的不适当激活 肠道细菌介导的TLR-IL-1 R信号通路参与了炎症性肠病的发病机制 疾病（IBD）和结肠炎相关癌症（CAC）。单个免疫球蛋白IL-1受体相关 Toll-IL-IR信号传导的负调节因子SIGIRR在肠道内稳态中起关键作用， 肠道炎症和结肠炎相关的肿瘤发生，通过维持微生物耐受性， 结肠上皮当SIGIRR在结肠上皮细胞中高度表达时， 在极化的Th 2和Th 17细胞中，表明SIGIRR在调节相互作用中的重要作用。 粘膜下层的上皮细胞和免疫细胞之间。这些结果表明，SIGIRR函数 作为结肠上皮细胞中的“守门人”和作为T细胞区室中的负“反馈对照”， 调节肠道菌群依赖性先天和适应性免疫应答。整体 假设SIGIRR在炎症诱导的肿瘤发生中起重要的调节作用， 结肠通过其对肠道微生物群依赖性稳态以及先天性和适应性免疫的影响 结肠上皮的反应。为了检验这一假设，提出了三个具体目标：（目标1） 阐明SIGIRR影响结肠稳态的分子机制 （目的2）确定SIGIRR在肠上皮细胞调控中的细胞类型特异性功能 （3）探讨SIGIRR对结肠肿瘤发生的影响机制。到 为了实现这些目标，一个重要的方法是分析细胞类型特异性SIGIRR缺陷对 肠道稳态、肠道炎症和结肠炎相关肿瘤发生。函数的读数 SIGIRR的范围将从原代细胞中TLR-1 L-1 R信号传导的生化分析到 使用结肠炎和结肠癌模型的体内先天性和适应性免疫应答。

Inflammatory bowel diseases (IBD) are associated with an elevated risk for colorectal cancer. Despite constant contact with the massive population of commensal bacteria, the colonic mucosa is normally hypo- responsive to these potentially proinflammatory threats. The intestinal epithelial layer functions not only as a physical barrier but also an innate and adaptive immune barrier against commensal bacteria. The long term objective is to understand how TLR-IL-1R signaling mediates the active cross-talk between the commensal and host to maintain tolerance of the colon epithelium to the commensal bacteria. Inappropriate activation of the TLR-IL-1R signaling by commensal bacteria contributes to the pathogenesis of inflammatory bowel diseases (IBD) and colitis-associated cancer (CAC). The single immunoglobulin IL-1 receptor related molecule (SIGIRR), a negative regulator for Toll-IL-IR signaling, plays a critical role in gut homeostasis, intestinal Inflammation and colitis-associated tumorigenesis by maintaining the microbial tolerance ofthe colonic epithelium. While SIGIRR Is highly expressed In colon epithelial cells, SIGIRR expression is Induced in polarized Th2 and Th17 cells, suggesting the important role of SIGIRR in modulafing the interplay between the epithelium and Immune cells in the submucosa. These results suggest that SIGIRR funcfions as a "Gate Keeper" in colon epithelial cells and as a negative "Feedback Control" in T cell compartment, modulating the commensal microflora-dependent innate and adaptive immune responses. The overall hypothesis is that SIGIRR plays an important regulatory role in inflammation-induced tumorigenesis in the colon through its impact on commensal microflora-dependent homeostasis and innate and adaptive immune responses ofthe colonic epithelium. To test this hypothesis, three speciflc aims are proposed: (Aim1) Elucidate the molecular mechanism by which SIGIRR exerts its impact on homeostasis ofthe colon epithelium; (Aim 2) Determine the cell-type specific function of SIGIRR in the control of intestinal inflammation; (Aim 3) Investigate the mechanism by which SIGIRR impacts on tumorigenesis in colon. To achieve the aims, one important approach is to analyze the Impact of cell-type specific SIGIRR deficiency on gut homeostasis, intestinal inflammation and colitis-associated tumorigenesis. The readouts forthe function of SIGIRR will be ranged from biochemical analyses of TLR-1L-1R signaling in primary cells to studies of innate and adaptive immune responses in vivo using colitis and colon cancer models.