NLR signaling 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是结直肠癌发生的易感因素。虽然CD和UC的确切病因尚不清楚，但人们普遍认为IBD的基础是针对共生微生物群的异常免疫反应。细胞外白介素受体(IL)和Toll样受体(TLR)家族的多种受体表达于胃肠道上皮细胞和免疫细胞上，与IBD的发生密切相关。最近，编码节点样受体(NLR)家族成员NOD2和Nlrp3的基因的单核苷酸多态(SNPs)与CD易感性有关。来自细菌的肽聚糖片段激活NOD2，从而触发适配蛋白RIP2的募集，导致K63连接的泛素化以及核因子-βB和MAP激酶信号的级联激活。我们的研究表明，NOD2和RIP2都是防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RIP2在激活核因子-kB途径方面位于NOD2的下游，但令人惊讶的是，我们的发现表明，NOD2和RIP2的作用以前没有明确和不同。总之，这项建议的主要目标是从机械上定义通过NOD2和RIP2信号调节结肠炎相关结直肠肿瘤发生的肠道免疫反应的分子基础。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，并为毁灭性的炎症性疾病创造了新的治疗选择。

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.