SIGIRR-mediated Tumor Suppression

炎症性肠病(IBD)与结直肠癌风险增加有关。尽管 由于不断接触大量的共生细菌，结肠粘膜通常处于低密度状态。 对这些潜在的促炎威胁作出反应。肠上皮层的功能不仅是 这不仅是一种物理屏障，也是对抗共生细菌的先天和适应性免疫屏障。从长远来看 目的是了解TLR-IL-1R信号如何介导共生体之间的主动串扰 和宿主以维持结肠上皮对共生细菌的耐受性。不适当地激活 共生菌TLR-IL-1R信号转导在炎症性肠病发病机制中的作用 疾病(IBD)和结肠炎相关癌症(CAC)。单个免疫球蛋白与IL-1受体相关 分子(SIGIRR)是Toll-IL-IR信号的负调控因子，在肠道内稳态中起着关键作用。 维持肠道微生物耐受性的肠炎和结肠炎相关肿瘤发生 结肠上皮。虽然SIGIRR在结肠上皮细胞中高表达，但SIGIRR的表达是被诱导的 在极化的Th2和Th17细胞中，提示SIGIRR在调节相互作用中发挥重要作用 在粘膜下层的上皮和免疫细胞之间。这些结果表明，SIGIRR函数 作为结肠上皮细胞的“守门人”和T细胞隔间的负“反馈控制”， 调节共生微生物群依赖的先天和获得性免疫反应。整体而言 假设SIGIRR在炎症诱导的肿瘤发生中起着重要的调节作用 结肠通过其对共生微生物区系依赖的动态平衡和先天免疫和获得性免疫的影响 结肠上皮的反应。为了验证这一假设，提出了三个特定的目标：(Aim1) 阐明SIGIRR影响结肠内稳态的分子机制 目的2：确定SIGIRR在肠道控制中的细胞类型特异性功能 炎症；(目的3)研究SIGIRR影响结肠肿瘤发生的机制。至 为了达到这一目的，一个重要的方法是分析细胞类型特异性SIGIRR缺陷对 肠道动态平衡、肠炎症和结肠炎相关肿瘤发生。该函数的读数 SIGIRR的研究将从原代细胞中TLR-1L-1R信号的生化分析到 使用结肠炎和结肠癌模型的体内先天和获得性免疫反应。

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.