NLR Regulation of Gastrointestinal Inflammation and Tumorigenesis

NLR 对胃肠道炎症和肿瘤发生的调节

• 批准号: 8468173
• 负责人: Irving C Allen
• 金额: $ 14.99万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8468173
• 关键词: Animals; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Beryllium; Binding; Cancer Model; Caspase-1; Cell Death; Cell physiology; Cells; Clinical; Colitis; Colon; Colon Carcinoma; Colorectal Cancer; Complex; Cytokine Signaling; Data; Development; Disease; Effectiveness; Environment; Experimental Models; Family; Family member; Generations; Goals; Hematopoietic; Immune; Immune response; Immune system; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interleukin-12; Interleukin-18; Leucine-Rich Repeat; Malignant Neoplasms; Mediating; Mediator of activation protein; Microbe; Modeling; Multiprotein Complexes; Mus; Nucleotides; Pathogenesis; Physiological; Predisposition; Prevention; Process; Production; Protein Family; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Stimulus; Stromal Cells; Subgroup; Testing; Tumor Promoters; Ulcerative Colitis; Work; attenuation; cancer cell; cancer type; cell type; colitis associated cancer; cytokine; environmental stressor; gastrointestinal; in vivo; inhibitor/antagonist; interest; leucine-rich repeat protein; medical complication; microbial; novel; pathogen; procaspase-1; protein complex; response; sensor; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Colorectal cancer is a serious medical complication for individuals suffering from ulcerative colitis and other inflammatory bowel diseases (IBDs). Signaling cascades which alter inflammatory activation are of specific relevance to the development of Colitis-associated Colorectal Cancer (CAC), as dysregulation of inflammation has been found to be associated with many types of cancers and inflammatory diseases. Our lab and others have recently characterized the NLR (NBD-LRR) family of proteins, which have been proven to be essential mediators of innate immune responses to microbes and environmental stressors. One subset of NLR family members have been shown to form multiprotein complexes, defined as inflammasomes, which can be further characterized by the specific NLR involved in formation. NLR inflammasomes function, in a cell type and stimuli specific manner, to process IL-12 and IL- 18 into mature cytokines. These proinflammatory cytokines have been implicated in IBDs and cancer. In addition to the inflammasome forming NLRs, a second sub-group of NLRs have been shown to function as negative regulators of inflammation through the modulation of NF-:B signaling. Dysregulation of NF-:B signaling is a critical component in the pathogenesis of inflammation and tumorigenesis in the gut. OBJECTIVES: Our working hypothesis proposes that the inflammasome associated NLR, NLRP3, and the anti-inflammatory NLR, NLRP12, both function to protect the host from ulcerative colitis and colitis associated cancer through the modulation of NF-:B signaling in innate immune cells. However, the NLRP1 inflammasome functions in either stromal or cancer cells to mediate inflammation and tumorigenesis through a mechanism that is independent of the NLRP3 protein. SPECIFIC AIM 1: Examine the contribution of the inflammasome components Pycard, Caspase-1 and NLRP1 in the development of EC and CAC. SPECIFIC AIM 2: Refine the mechanisms by which NLRP3 mediates its physiological effects on EC and CAC. SPECIFIC AIM 3: Evaluate the ability of NLRP12 to function as a negative regulator of tumorigenesis during CAC through its ability to suppress non-canonical NF-:B signaling. STUDY DESIGN: We will utilize genetically manipulated mice lacking specific NLRs or inflammasome components to evaluate function in models of inflammatory bowel disease and cancer. Aim 1 will test the hypothesis that the attenuation mediated by Pycard and Caspase-1 during EC and CAC cannot be attributed to NLRP3, which suggests another NLR inflammasome. Here, we will test the components of the NLRP1 inflammasome as a potential candidate. Aim 2 will test the hypothesis that NLRP3 attenuation during EC and CAC is associated with the suppression of IL-12 and IL-18 through the modulation, either direct or indirect, of canonical NF-:B activity. Aim 3 will test the hypothesis that NLRP12 functions as a negative regulator of non-canonical NF-:B signaling to attenuate inflammation and protect the host during EC and CAC.

描述（由申请人提供）：对于患有溃疡性结肠炎和其他炎症性肠病（IBD）的个体来说，结直肠癌是一种严重的医疗并发症。改变炎症激活的信号级联与结肠炎相关结直肠癌（CAC）的发展特别相关，因为已发现炎症失调与许多类型的癌症和炎症性疾病有关。我们的实验室和其他实验室最近对 NLR (NBD-LRR) 蛋白质家族进行了表征，该家族已被证明是对微生物和环境压力源的先天免疫反应的重要介质。 NLR 家族成员的一个子集已被证明可形成多蛋白复合物，定义为炎性小体，其可以通过参与形成的特定 NLR 进一步表征。 NLR 炎症小体以细胞类型和刺激特异性方式发挥作用，将 IL-12 和 IL-18 加工成成熟细胞因子。这些促炎细胞因子与 IBD 和癌症有关。除了形成 NLR 的炎症小体之外，NLR 的第二个亚组已被证明通过调节 NF-:B 信号传导发挥炎症负调节因子的作用。 NF-:B 信号传导失调是肠道炎症和肿瘤发生的关键组成部分。目的：我们的工作假设提出，炎症小体相关的 NLR（NLRP3）和抗炎 NLR（NLRP12）均通过调节先天免疫细胞中的 NF-:B 信号传导来保护宿主免受溃疡性结肠炎和结肠炎相关癌症的侵害。然而，NLRP1 炎症小体在基质细胞或癌细胞中发挥作用，通过独立于 NLRP3 蛋白的机制介导炎症和肿瘤发生。具体目标 1：检查炎症小体成分 Pycard、Caspase-1 和 NLRP1 在 EC 和 CAC 发展中的贡献。具体目标 2：完善 NLRP3 介导其对 EC 和 CAC 生理作用的机制。具体目标 3：评估 NLRP12 通过抑制非典型 NF-:B 信号传导的能力，在 CAC 期间作为肿瘤发生负调节因子发挥作用。研究设计：我们将利用缺乏特定 NLR 或炎症小体成分的基因操纵小鼠来评估炎症性肠病和癌症模型中的功能。目标 1 将检验以下假设：EC 和 CAC 期间由 Pycard 和 Caspase-1 介导的衰减不能归因于 NLRP3，这表明存在另一种 NLR 炎性体。在这里，我们将测试 NLRP1 炎症小体的成分作为潜在候选者。目标 2 将检验以下假设：EC 和 CAC 期间 NLRP3 减弱与通过直接或间接调节典型 NF-:B 活性来抑制 IL-12 和 IL-18 相关。目标 3 将检验以下假设：NLRP12 作为非经典 NF-:B 信号传导的负调节因子，可在 EC 和 CAC 期间减轻炎症并保护宿主。