NLR signaling 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易导致结直肠癌的发展。虽然CD和UC的确切病因尚不清楚，但针对肠道微生物菌群的异常免疫应答被广泛认为是IBD的基础。细胞外白细胞介素（IL）受体和Toll样受体（TLR）家族的多种受体在胃肠道的上皮细胞和免疫细胞上表达，并与IBD有关。最近，编码NOD样受体（NLR）家族成员Nod 2和Nlrp 3的基因中的单核苷酸多态性（SNP）与CD易感性相关。来自细菌的肽聚糖片段激活Nod 2，其触发衔接蛋白Rip 2的募集，导致K63连接的泛素化和NF-κ B的激活。B和MAP激酶信号级联。我们的研究表明，Nod 2和Rip 2都是阻止肠道炎症和结直肠肿瘤发生中破坏性炎症免疫反应的关键调节因子。然而，尽管Rip 2在激活NF-κ B通路中位于Nod 2的下游，但令人惊讶的是，我们的研究结果表明Nod 2和Rip 2先前未定义和不同的作用。总而言之，本提案的主要目标是机械地定义Nod 2和Rip 2信号传导对结肠炎相关结肠直肠肿瘤发生的肠道免疫应答的潜在调节的分子基础。拟议的研究深入了解了NLR/Nod 2/Rip 2参与IBD和结直肠肿瘤发生的关键重叠和非重叠分子机制，并为毁灭性炎症性疾病创造了新的治疗选择。 公共卫生相关性：先天免疫系统被认为介导肠道炎症和致癌的发展。然而，不同的先天免疫信号通路在炎症和结直肠肿瘤发生发展中的作用尚未阐明。拟议的研究将有助于我们深入了解Nod 2和Rip 2参与IBD和结直肠肿瘤发生的关键分子机制，并为毁灭性炎症性疾病创造新的治疗选择。

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 to the development of colorectal cancer. Although the precise etiology of CD and UC remains unclear, aberrant immune responses against commensal microflora are widely thought to underlie IBD. Multiple receptors of the extracellular interleukin (IL) receptor and Toll-like receptor (TLR) families are expressed on epithelial and immune cells in the gastro-intestinal tract and have been implicated in IBD. More recently, single nucleotide polymorphisms (SNPs) in the genes encoding the NOD-like receptor (NLR) family members Nod2 and Nlrp3 were linked to CD susceptibility. Peptidoglycan fragments from bacteria activate Nod2, which triggers recruitment of the adaptor protein Rip2 resulting in K63- linked ubiquitylation and activation of NF-?B and MAP kinase signaling cascades. Our studies show that both Nod2 and Rip2 are critical regulators preventing destructive inflammatory immune responses in the intestinal inflammation and colorectal tumorigenesis. However, although Rip2 is downstream of Nod2 in activating NF-kB pathway, surprisingly, our findings indicate previously undefined and divergent roles for Nod2 and Rip2. Altogether, the major goals of this proposal are to mechanistically define the molecular basis underlying regulation of intestinal immune response to colitis-associated colorectal tumorigenesis by Nod2 and Rip2 signaling. The proposed studies give insight into the key overlapping and non-overlapping molecular mechanisms by which NLR/Nod2/Rip2 participate in IBD and colorectal tumorigenesis and create new therapeutic options for devastating inflammatory diseases. PUBLIC HEALTH RELEVANCE: Innate immune system has been suggested to mediate the development of intestinal inflammation and carcinogenesis. Nonetheless, the role of distinct innate immune signaling pathways in the development of inflammation and colorectal tumorigenesis is yet to be unraveled. The proposed studies will contribute to our insight into the key molecular mechanisms by which Nod2 and Rip2 participate in IBD and colorectal tumorigenesis and create new therapeutic options for devastating inflammatory diseases.