Colitis, colon cancer and the NLR family

炎症性肠病(IBD)是结直肠癌(CRC)发生的重要危险因素，结直肠癌是美国癌症相关死亡的主要原因。IBD和CRC通常与炎性细胞因子的过度产生有关，炎性细胞因子受多种细胞信号通路的激活调节，包括转录因子NF-kB家族、IL-1、COX2和IL6。NLR(核苷酸结合域和富含亮氨酸的重复序列或Nod样受体)家族在IBD的研究中受到了极大的关注，因为它们在调节炎症中的作用以及某些NLR蛋白与克罗恩病的遗传关联。NLR是一个多成员基因家族，编码一组胞浆蛋白，参与微生物产物的细胞内传感以及与损伤相关的分子模式。因此，NLR家族成员是先天免疫反应的重要调节者，先天免疫反应是IBD和CRC的重要环节。我们和其他人已经开始在实验性结肠炎(EC)和结肠炎相关结肠癌(CAC)模型中显示炎症体相关NLR的关联。这组蛋白质对病原体衍生的产物做出反应，并可以与关键的NLR接头蛋白ASC(带有卡片的凋亡斑点包含蛋白)一起组装成炎症体，以激活IL-1B处理酶caspase-1。Caspase-1的激活导致前IL-1B和IL-18的裂解和成熟。除了对EC和CAC模型中这些研究良好的炎性小体成分的分析外，我们有数据表明，其他具有抗炎功能的NLRs在这些模型中具有很强的作用，并可以减轻临床结果。这项提案计划研究ASC和这些其他NLR在这些疾病模型中的作用。我们将进一步描述这些蛋白影响疾病结局的分子机制。

Inflammatory bowel disease (IBD) is a significant risk factor in the development of colorectal cancer (CRC), a leading contributor to cancer-related deaths in the United States. Both IBD and CRC are commonly associated with the exaggerated production of inflammatory cytokines which are regulated by the activation of various cell signaling pathways including the NF-kB family of transcription factors, IL-1, COX2 and IL6. The NLR (nucleotide binding domain and leucine-rich-repeat-containing or NOD-like receptor) family of proteins has received much attention in IBD research due to their role in regulating inflammation and the genetic association of certain NLR proteins with Crohns' disease. NLR is a multi-member gene family that encodes a group of cytosolic proteins that are involved in the intracellular sensing of microbial products as well as damage-associated molecular patterns. Thus NLR family members are crucial regulators of innate immune response which is an important link to IBD and CRC. We and others have begun to show the association of the inflammasome-associated NLRs in models of experimental colitis (EC) and colitis-associated colon cancer (CAC). This group of proteins respond to pathogen derived products and can assemble into inflammasomes in conjunction with the key NLR adaptor protein, ASC (apoptotic speck containing protein with a CARD) to activate the IL-1B-processing enzyme caspase-1. Caspase-1 activation then leads to the cleavage and maturation of pro- IL-1B and IL-18. In addition to the analyses of these well- studied inflammasome components in models of EC and CAC, we have data to indicate a strong role for other NLRs which have anti-inflammatory functions, and can attenuate the clinical outcome in these models. This proposal plans to examine the roles of ASC and these other NLRs in these disease models. We will further delineate the molecular mechanisms by which these proteins affect disease outcome.