Innate signaling pathways in colitis and colorectal tumorigenesis

 描述(申请人提供)：炎症性肠病(IBD)，如克罗恩病(CD)和溃疡性结肠炎(UC)是发达国家的主要健康问题。此外，IBD使患者更容易发生结直肠癌。虽然CD和UC的确切病因尚不清楚，但针对共生微生物区系的异常免疫反应被广泛认为是IBD发病的基础。Toll样受体(TLR)、结节样受体(NLRs)和胞浆DNA感受器家族的多个受体在胃肠道的上皮细胞和免疫细胞上表达，并与IBD和结直肠癌有关。我们实验室和其他实验室的研究表明，NLRs和胞浆DNA传感器在预防肿瘤发生方面发挥了重要作用。I型干扰素信号可以被一个或多个这些受体激活。重要的是，编码NLR、胞质DNA传感器和干扰素信号通路分子的基因的单核苷酸多态(SNPs)与结直肠癌的易感性有关。然而，介导这种保护的I型干扰素所控制的下游效应机制还不是很清楚。在这个方案中，我们证明了干扰素调节因子1(IRF1)，它是响应I型干扰素信号而诱导的， 对于防止肠道的破坏性炎症免疫反应和相关的肿瘤发生至关重要。这项建议的主要目标是从机械上定义IRF1调控结肠炎和结直肠肿瘤发生的细胞和分子基础。拟议的研究将为这些毁灭性的炎症性疾病带来新的治疗选择。

 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.