Colitis, colon cancer and the NLR family

炎症性肠病（IBD）是结直肠癌（CRC）发展的重要危险因素，结直肠癌是美国癌症相关死亡的主要原因。IBD和CRC通常都与炎症细胞因子的过度产生有关，炎症细胞因子受多种细胞信号通路的激活调节，包括NF-kB转录因子家族、IL-1、COX2和il - 6。NLR（核苷酸结合域和富含亮氨酸的重复序列或nod样受体）蛋白家族在IBD研究中受到了广泛关注，因为它们在调节炎症和某些NLR蛋白与克罗恩病的遗传关联中的作用。NLR是一个多成员基因家族，它编码一组细胞质蛋白，这些蛋白参与细胞内微生物产物的感知以及与损伤相关的分子模式。因此，NLR家族成员是先天性免疫反应的重要调节因子，而先天性免疫反应是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）和结肠炎相关性结肠癌（CAC）模型中显示炎症小体相关NLRs的关联。这组蛋白对病原体衍生的产物作出反应，并可以与关键的NLR适配蛋白ASC（凋亡斑点含卡蛋白）一起组装成炎症小体，激活il -12加工酶caspase-1。Caspase-1的激活导致IL-12和IL-18的裂解和成熟。除了对这些在EC和CAC模型中得到充分研究的炎性体成分进行分析外，我们有数据表明，其他具有抗炎功能的nlr也有很强的作用，并且可以减轻这些模型中的临床结果。本提案计划检查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-12-processing enzyme caspase-1. Caspase-1 activation then leads to the cleavage and maturation of pro- IL-12 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.