Understanding Nlrp6 function in inflammatory monocytes during inflammation and tumorigenesis

了解炎症和肿瘤发生过程中炎症单核细胞中 Nlrp6 的功能

• 批准号: 9123331
• 负责人: Sergey S Seregin
• 金额: $ 5.68万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9123331
• 关键词: Adoptive Transfer; Animal Model; Azoxymethane; Bacteria; Bone Marrow; Carcinogens; Cells; Chimera organism; Chronic; Colitis; Colon; Colon Carcinoma; Data; Development; Diffuse; Disease; Epithelial; Epithelial Cells; Family; Germ-Free; Health; Hematopoietic; Hemorrhagic colitis; IL18 gene; Immune response; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interleukin-18; Intestines; Kinetics; Knowledge; Lead; Malignant neoplasm of gastrointestinal tract; Mediating; Mediator of activation protein; Mission; Mus; Outcome; Pathogenesis; Pattern recognition receptor; Peptides; Phenotype; Population; Predisposition; Prevention strategy; Production; Public Health; Risk Factors; Role; Scheme; Signal Transduction; Sodium Dextran Sulfate; TNF gene; Testing; Ulcerative Colitis; Weight; antimicrobial; cell injury; colitis associated cancer; cytokine; effective therapy; gut microbiome; gut microbiota; improved; intestinal homeostasis; microbial; microbiome; microbiota; monocyte; mortality; prevent; receptor; repaired; research study; response; therapeutic target; tumor; tumorigenesis

 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.

 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，并且由于对疾病发病机制的不完全了解，一直缺乏治疗或预防这些疾病的有效治疗方法。 Nlrp6 属于参与微生物和损伤信号识别的模式识别受体家族，已被证明可以预防结肠炎和肿瘤发生。骨髓嵌合体实验表明，造血室中 Nlrp6 的表达有助于防止小鼠炎症相关肿瘤的发展；然而，哪些特定细胞群导致这种 Nlrp6 依赖性表型仍不清楚。我们现在有初步数据表明炎症单核细胞对于 Nlrp6 介导的结肠炎保护很重要。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群的组成，因此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标进行检验：1）确定 Ly6Chi 炎症单核细胞中 Nlrp6 活性预防 DSS 诱导的结肠炎和结肠炎相关肿瘤发生的机制；2）研究炎症单核细胞中的 Nlrp6 功能是否调节肠道微生物组以应对炎症。我们的研究将进一步阐明 Nlrp6 限制炎症和肿瘤发生的机制，这可能会带来新的预防或治疗策略。