NLR signaling in colitis and colorectal tumorigenesis

描述（由申请人提供）：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易导致结直肠癌的发生。虽然CD和UC的确切病因尚不清楚，但对共生菌群的异常免疫反应被广泛认为是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上皮细胞和免疫细胞上表达，并与IBD有关。最近，nod样受体（NLR）家族成员Nod2和Nlrp3编码基因的单核苷酸多态性（snp）与CD易感性有关。来自细菌的肽聚糖片段激活Nod2，从而触发接头蛋白Rip2的募集，导致K63连接的泛素化和NF-？B和MAP激酶信号级联。我们的研究表明，Nod2和Rip2在肠道炎症和结直肠肿瘤发生中都是阻止破坏性炎症免疫反应的关键调节因子。然而，尽管Rip2在激活NF-kB通路中位于Nod2的下游，但令人惊讶的是，我们的研究结果表明Nod2和Rip2在之前未定义的和不同的作用。总之，本研究的主要目标是通过Nod2和Rip2信号，从机制上确定肠道免疫应答对结肠炎相关结直肠肿瘤发生调节的分子基础。这些研究揭示了NLR/Nod2/Rip2参与IBD和结直肠肿瘤发生的关键重叠和非重叠分子机制，并为破坏性炎症性疾病的治疗提供了新的选择。

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.