Understanding Nlrp6 function in inflammatory monocytes during inflammation and tumorigenesis

 描述（由申请人提供）：炎症性肠病和炎症相关结肠癌是主要的公共卫生问题，部分由于对疾病发病机制的不完全理解，一直缺乏治疗或预防这些疾病的有效治疗方法。nlrp 6属于参与识别微生物和损伤信号的模式识别受体家族，已被证明对结肠炎和肿瘤发生具有保护作用。骨髓嵌合体实验表明，Nlrp 6在造血隔室中的表达有助于保护小鼠免受炎症相关的肿瘤发展;然而，什么特定的细胞群负责这种Nlrp 6依赖性表型仍然未被确定。我们现在有初步的数据表明，炎症单核细胞是重要的Nlrp 6介导的保护结肠炎。由于Nlrp 6已被证明可以调节炎症反应、IL-18产生和肠道微生物群的组成，我们假设炎症单核细胞中的Nlrp 6活性通过促进上皮修复和调节肠道微生物群的组成来调节肠道稳态。我们的中心假设将通过以下具体目的进行测试：1）确定Ly 6Chi炎性单核细胞中的Nlrp 6活性保护免受DSS诱导的结肠炎和结肠炎相关肿瘤发生的机制，以及2）研究炎性单核细胞中的Nlrp 6功能是否响应于炎症调节肠道微生物组。我们的研究将进一步阐明Nlrp 6限制炎症和肿瘤发生的机制，这可能会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.