Innate signaling pathways in colitis and colorectal tumorigenesis

 描述（由申请人提供）：克罗恩病（CD）和溃疡性结肠炎（UC）等炎症性肠道疾病（IBD）构成发达国家的主要健康问题。此外，IBD使患者易于发生结直肠癌。虽然CD和UC的确切病因尚不清楚，但针对肠道微生物群的异常免疫应答被广泛认为是IBD发病机制的基础。Toll样受体（TLR）、Nod样受体（NLR）和胞质DNA传感器家族的多种受体在胃肠道中的上皮细胞和免疫细胞上表达，并且与IBD和结肠直肠癌有关。我们实验室和其他实验室的研究表明，NLR和胞质DNA传感器在预防肿瘤发生中发挥重要作用。I型干扰素信号传导可以被一种或多种这些受体激活。重要的是，编码NLR、胞质DNA传感器和干扰素信号传导途径分子的基因中的单核苷酸多态性（SNP）与结直肠癌的易感性有关。然而，介导这种保护的I型干扰素调控的下游效应机制还不清楚。在这个建议中，我们表明干扰素调节因子1（IRF1），这是诱导响应I型干扰素信号， 对于预防肠道中的破坏性炎症免疫反应和相关的肿瘤发生至关重要。该提案的主要目标是机械地定义IRF1对结肠炎和结直肠肿瘤发生的潜在调节的细胞和分子基础。拟议的研究将为这些毁灭性的炎症性疾病产生新的治疗选择。

 DESCRIPTION (provided by applicant): Inflammatory bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC) constitute a major health problem in developed countries. Moreover, IBD predisposes patients to the development of colorectal cancer. Although the precise etiology of CD and UC remains unclear, aberrant immune responses against commensal microbiota are widely thought to underlie the pathogenesis of IBD. Multiple receptors of the Toll- like receptors (TLR), Nod-like receptors (NLRs) and cytosolic DNA sensors families are expressed on epithelial and immune cells in the gastrointestinal tract and have been implicated in IBD and colorectal cancer. Research studies by our lab and others have shown an important role for NLRs and cytosolic DNA sensors in the prevention of tumorigenesis. Type I interferon signaling can be activated by one or more these receptors. Importantly, single nucleotide polymorphisms (SNPs) in the genes encoding NLRs, cytosolic DNA sensors and molecules of the interferon-signaling pathway are linked to susceptibility to colorectal cancer. However, the downstream effector mechanisms governed by type I interferons that mediate this protection are not well understood. In this proposal, we show that interferon regulatory factor 1 (IRF1), which is induced in response to type I interferon signaling, is critical for preventing destructive inflammatory immune responses and associated tumorigenesis in the intestine. The major goal of this proposal is to mechanistically define the cellular and molecular basis underlying regulation of colitis and colorectal tumorigenesis by IRF1. The proposed studies will generate new therapeutic options for these devastating inflammatory diseases.