Regulation of intestinal inflammation and tumorigenesis by Nlrp6

描述（由申请人提供）：结直肠癌是美国男性和女性的第三大常见癌症。患结肠癌的风险最高的人群是那些有遗传倾向的人和那些患有炎症性肠病的人。对于患有炎症性肠病的个体，风险与影响结肠的炎症的程度和持续时间相关，并且与正常个体相比可以增加5至15倍。炎症相关结肠癌的小鼠模型已经证明，肠道细菌和宿主免疫系统可以调节肠道炎症和癌变。特别是，Nod样受体家族的成员已经成为肠道炎症和癌症发展的重要参与者。NLR是细胞内模式识别受体，其参与感测肠道内的致病菌和寄生菌。我们最近发现了一个相对未知的NLR家族成员，Nlrp 6，这是重要的肠内稳态和肿瘤抑制在结肠内的慢性损伤和炎症。然而，Nlrp 6减少结肠中肿瘤发展和炎症的机制仍有待阐明。我们假设Nlrp 6通过调节肠道微生物群的组成和IL-18的产生来调节对肠道炎症和肿瘤发生的易感性。我们的具体目标是：（1）确定Nlrp 6在调节肠道微生物组以增加对结肠炎症和癌症的易感性方面的重要性，（2）鉴定Nlrp 6发挥作用以抑制肿瘤发生的细胞类型，以及3）了解IL-18在Nlrp 6介导的肿瘤抑制中的作用。这些研究的长期目标是增加我们对NLR和肠道微生物群之间的相互作用如何调节结肠癌发生的理解，这可能导致结肠癌的新化学预防策略，包括操纵肠道细菌和/或调节NLR信号通路。

DESCRIPTION (provided by applicant): Colorectal cancer is the third most common cancer in both men and women in the United States. The highest risk groups for developing colon cancer are those with a genetic predisposition and those with inflammatory bowel disease. For individuals with inflammatory bowel disease, the risk correlates with extent and duration of inflammation affecting the colon and can be increased 5- to 15-fold compared to normal individuals. Mouse models of inflammation-related colon cancer have demonstrated that intestinal bacteria and the host immune system can regulate intestinal inflammation and carcinogenesis. In particular, members of the Nod-like receptor family have emerged as important players in the development of intestinal inflammation and cancer. NLRs are intracellular pattern-recognition receptors that are involved in the sensing of both pathogenic and commensal bacteria within the gut. We have recently identified a relatively unknown member of the NLR family, Nlrp6, which is important for intestinal homeostasis and tumor suppression during chronic injury and inflammation within the colon. However, the mechanism by which Nlrp6 reduces tumor development and inflammation in the colon remains to be elucidated. We hypothesize that Nlrp6 modulates susceptibility to intestinal inflammation and tumorigenesis by regulating the composition of the gut microbiota and the production of IL-18. Our specific aims are: (1) to determine the importance of Nlrp6 in regulating the gut microbiome to increase susceptibility to colonic inflammation and cancer, (2) to identify the cell type that Nlrp6 functions in to suppress tumorigenesis, and 3) to understand the role of IL-18 in Nlrp6-mediated tumor suppression. The long-term goal of these studies is to increase our understanding of how interactions between NLRs and the gut microbiota regulate colon carcinogenesis, which may lead to novel chemopreventive strategies for colon cancer involving the manipulation of the intestinal bacteria and/or modulation of NLR signaling pathways.