Colitis, colon cancer and the NLR family

炎症性肠病（IBD）是结直肠癌（CRC）发展的重要风险因素，CRC是美国癌症相关死亡的主要原因。IBD和CRC两者通常与炎性细胞因子的过度产生相关，所述炎性细胞因子通过各种细胞信号传导途径的激活来调节，所述细胞信号传导途径包括转录因子的NF-kB家族、IL-1、C 0X 2和IL 6。NLR（nucleotide binding domain and leucine-rich-repeat-containing or NOD-like receptor）蛋白家族由于其在炎症调节中的作用以及某些NLR蛋白与克罗恩病的遗传相关性而在IBD研究中受到广泛关注。NLR是一个多成员基因家族，编码一组细胞溶质蛋白，这些蛋白参与微生物产物的细胞内传感以及损伤相关的分子模式。因此，NLR家族成员是先天免疫应答的关键调节剂，先天免疫应答是IBD和CRC的重要联系。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）模型中显示炎性小体相关NLR的相关性。这组蛋白质响应于病原体衍生的产物，并且可以与关键的NLR衔接蛋白ASC（具有CARD的含凋亡斑点的蛋白质）结合组装成炎性体，以激活IL-1B加工酶半胱天冬酶-1。半胱天冬酶-1活化然后导致IL-1B原和IL-18原的裂解和成熟。除了在EC和CAC模型中分析这些充分研究的炎性体组分之外，我们有数据表明具有抗炎功能的其他NLR的强作用，并且可以减弱这些模型中的临床结果。该提案计划研究ASC和这些其他NLR在这些疾病模型中的作用。我们将进一步阐明这些蛋白质影响疾病结果的分子机制。

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.