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: 8572668
• 负责人: Irving C Allen
• 金额: $ 9.07万
• 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/8572668
• 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）：大肠癌是患有溃疡性结肠炎和其他炎症性肠病（IBD）的患者的严重医学并发症。改变炎症激活的信号级联反应与结肠炎相关结直肠癌（CAC）的发展具有特定的相关性，因为已经发现炎症失调与多种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表征了NLR（NBD-LRR）蛋白质家族，这些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必要介体。 NLR家族成员的一个子集已被证明形成了多蛋白络合物，该复合物被定义为炎症，可以进一步以与形成相关的特定NLR进行表征。 NLR炎性症以细胞类型和刺激方式的功能，将IL-12和IL-18处理成成熟的细胞因子。这些促炎细胞因子与IBD和癌症有关。除了形成NLR的炎性体外，第二个NLR的第二个亚组通过调节NF-：B信号传导作用可作为炎症的负调节剂。 NF-：B信号的失调是肠道炎症和肿瘤发生发病机理的关键成分。目的：我们的工作假设提出，炎症体相关的NLR，NLRP3和抗炎NLR，NLRP12，既可以通过调节先天免疫细胞中的NF-：B信号来保护宿主免受溃疡性结肠炎和结肠炎的癌症。然而，NLRP1炎症体在基质或癌细胞中的功能通过独立于NLRP3蛋白的机制介导炎症和肿瘤发生。特定目的1：检查炎性组成分Pycard，caspase-1和NLRP1在EC和CAC开发中的贡献。具体目标2：完善NLRP3介导其生理影响对EC和CAC的机制。具体目标3：通过抑制非典型的NF-：B信号传导的能力，评估NLRP12在CAC期间起作用的负调节剂的能力。研究设计：我们将利用缺乏特定NLR或炎性组成分的遗传操纵小鼠来评估炎症性肠病和癌症模型中的功能。 AIM 1将检验以下假设：EC和CAC期间Pycard和Caspase-1介导的衰减不能归因于NLRP3，这表明另一种NLR炎症体。在这里，我们将测试NLRP1炎性小体的组成部分，作为潜在的候选者。 AIM 2将检验以下假设：EC和CAC期间的NLRP3衰减与经典nf-：B活性的调制（直接或间接）的抑制与IL-12和IL-18的抑制有关。 AIM 3将检验以下假设：NLRP12作为非典型NF-：B信号传导的负调节剂，以减轻EC和CAC期间的宿主。