Understanding Nlrp6 function in inflammatory monocytes during inflammation and tumorigenesis

 描述(申请人提供)：炎症性肠病和炎症性结肠癌是主要的公共卫生问题，缺乏有效的治疗或预防这些疾病的方法，部分原因是对疾病发病机制的了解不完全。NLRP6属于模式识别受体家族，参与识别微生物和损伤信号，已被证明对结肠炎和肿瘤发生有保护作用。骨髓嵌合体实验表明，NLRP6在造血室的表达有助于防止小鼠炎症相关肿瘤的发展；然而，什么特定细胞群(S)对这种NLRP6依赖的表型负责尚不清楚。我们现在有初步数据表明，炎性单核细胞对NLRP6介导的结肠炎保护作用很重要。由于NLRP6已被证明可以调节炎症反应、IL-18的产生和肠道微生物区系的组成，我们假设炎症单核细胞中的NLRP6活性通过促进上皮修复和调节肠道微生物区系的组成来调节肠道动态平衡。我们的中心假设将通过以下具体目标进行验证：1)确定Ly6chi炎性单核细胞中NLRP6活性对DSS诱导的结肠炎和结肠炎相关肿瘤发生的保护机制；2)研究炎性单核细胞中的NLRP6功能是否调节肠道微生物群对炎症的反应。我们的研究将进一步阐明NLRP6限制炎症和肿瘤形成的机制，这可能导致新的预防或治疗策略。

 DESCRIPTION (provided by applicant): Inflammatory bowel disease and inflammation-associated colon cancer are major public health problems and effective treatments to treat or prevent these diseases have been lacking in part due to an incomplete understanding of disease pathogenesis. Nlrp6, which belongs to a family of pattern recognition receptors involved in the recognition of microbial and damage signals, has been demonstrated to be protective against colitis and tumorigenesis. Bone marrow chimera experiments have suggested that expression of Nlrp6 in the hematopoietic compartment contributed to protection against inflammation-associated tumor development in mice; however, what specific cell population(s) are responsible for this Nlrp6-dependent phenotype remain unidentified. We now have preliminary data suggesting that inflammatory monocytes are important for Nlrp6-mediated protection against colitis. Since Nlrp6 has been shown to regulate inflammatory responses, IL-18 production, and the composition of the gut microbiota, we hypothesize that Nlrp6 activity in inflammatory monocytes regulates intestinal homeostasis by promoting epithelial repair and modulating the composition of the gut microbiota. Our central hypothesis will be tested by the following specific aims: 1) to determine the mechanism by which Nlrp6 activity in Ly6Chi inflammatory monocytes protects against DSS-induced colitis and colitis- associated tumorigenesis and 2) to investigate whether Nlrp6 function in inflammatory monocytes regulates the gut microbiome in response to inflammation. Our studies will further clarify mechanisms by which Nlrp6 limits inflammation and tumorigenesis, which may lead to new strategies for prevention or treatment.