Evaluating NLR Modulation of Canonical and Non-Canonical NF-kB Signaling in IBD

评估 IBD 中规范和非规范 NF-kB 信号传导的 NLR 调制

• 批准号: 8943147
• 负责人: Irving C Allen
• 金额: $ 8.05万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8943147
• 关键词: Address; American; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Area; Attenuated; Autoimmune Diseases; Biological Process; CD4 Positive T Lymphocytes; CXCL13 gene; Cells; Chronic; Colitis; Crohn' s disease; Data; Development; Disease; Evaluation; Family; Future; Genetic Transcription; Goals; Health; Healthcare; Homeostasis; Human; IRAK1 gene; Immune system; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Knockout Mice; Lead; Literature; Mediating; Modeling; Mus; Myelogenous; Myeloid Cells; NF-kappa B; Pathogenesis; Pathway interactions; Patients; Pattern recognition receptor; Phosphorylation; Phosphotransferases; Physiological; Play; Production; Property; Proteins; Regulation; Regulator Genes; Relative (related person); Research Project Grants; Role; Signal Pathway; Signal Transduction; Sodium Dextran Sulfate; Ulcerative Colitis; Work; attenuation; cell type; chemokine; cytokine; gastrointestinal; gastrointestinal system; infliximab; inhibitor/antagonist; intestinal crypt; intestinal villi; member; mouse model; multicatalytic endopeptidase complex; novel; novel therapeutics; pre-clinical; receptor function; recombinase; signal processing; tumor; tumorigenesis; villin

DESCRIPTION (provided by applicant): Crohn's disease (CD) and ulcerative colitis (UC) are common manifestations of inflammatory bowel disease (IBD). These two debilitating disorders afflict approximately 1.4 million Americans and over 4 million people worldwide. Previous work from our lab has identified a novel sub-group of cellular proteins from the NLR family of pattern recognition receptors that function to negatively regulate inflammation and tumor development during IBD. We have previously shown that the NLR NLRP12 is a potent modulator of experimental colitis and inflammation driven tumorigenesis in pre-clinical mouse models. During IBD, NLRP12 modulates gastrointestinal inflammation through the attenuation of either canonical or non-canoincal NF-κB signaling. While the role of the canonical NF-κB signaling pathway during IBD is well established, the contribution of the non-canonical NF-κB cascade is relatively uncharacterized. Our previous findings indicate that a pair of chemokines associated with non-canonical NF-κB signaling is significantly up-regulated in the absence of NLRP12 and associated with increased IBD pathobiology in mice. These same chemokines are also dysregulated in human IBD patients. For example, our preliminary data revealed that the NLRP12 regulated chemokine CXCL13 is up-regulated 42- and 23-fold in CD and UC patients that are unresponsive to infliximab, respectively. Together, these data illustrate the importance of NLRP12 and non-canonical NF-κB signaling during IBD; however, the underlying mechanism/s is still unresolved. One hypothesis suggests that NLRP12 attenuates canonical NF-κB signaling during IBD; whereas, a second hypothesis that is supported by our preliminary data, indicates that NLRP12 inhibits the non-canoncial NF-κB signaling cascade. The apparent discrepancies in the hypothesized mechanisms can be reconciled by considering that the canonical NF-κB pathway can be significantly influenced by noncanoncial NF-κB signaling. Likewise, it is possible that these pathways are differentially modulated through cell type and/or temporal specific mechanisms that can significantly impact IBD pathogenesis. Here, I propose an extension to research project (K01-DK092355) to better evaluate these two prevailing hypotheses. The overall goal of this proposal is to generate a panel of mice that are deficient in canonical and non-canonical NF-κB signaling following cell specific Cre-recombinase disruption to better characterize the mechanism associated with NLRP12 modulation of IBD. NLRs with negative regulatory functions, such as NLRP12, and non-canonical NF-κB signaling during IBD represent areas that are currently understudied and not well defined. The mouse lines and data generated by the proposed studies will serve as preliminary data for a future R01 submission. The evaluation of these unique pathways in the context of IBD represent a novel direction that will contribute to future discoveries associated with immune system homeostasis in the gut and lead to new therapeutic strategies targeting these diseases.

描述（由申请人提供）：克罗恩病 (CD) 和溃疡性结肠炎 (UC) 是炎症性肠病 (IBD) 的常见表现，这两种使人衰弱的疾病困扰着大约 140 万美国人和全世界超过 400 万人。已经从模式识别受体 NLR 家族中鉴定出一个新的细胞蛋白亚组，其功能是在 IBD 期间负向调节炎症和肿瘤发展。 NLRP12 是临床前小鼠模型中实验性结肠炎和炎症驱动的肿瘤发生的有效调节剂，在 IBD 过程中，NLRP12 通过减弱经典或非经典 NF-κB 信号传导来调节胃肠道炎症，同时发挥经典 NF-κB 的作用。 IBD 期间的信号传导通路已被充分确立，但非经典 NF-κB 级联的贡献相对未得到表征。研究结果表明，在 NLRP12 缺失的情况下，与非经典 NF-κB 信号传导相关的一对趋化因子显着上调，并且与小鼠 IBD 病理学的增加相关。这些相同的趋化因子在人类 IBD 患者中也出现失调。初步数据显示，NLRP12 调节的趋化因子 CXCL13 在对药物无反应的 CD 和 UC 患者中上调 42 倍和 23 倍。这些数据分别说明了 NLRP12 和非典型 NF-κB 信号传导在 IBD 期间的重要性；然而，一种假设表明 NLRP12 会减弱 IBD 期间的典型 NF-κB 信号传导。 ，我们的初步数据支持的第二个假设表明 NLRP12 抑制非典型 NF-κB 信号级联。考虑到经典 NF-κB 通路可能受到非经典 NF-κB 信号传导的显着影响，可以协调所培养机制中的差异。类似地，这些通路可能通过细胞类型和/或时间特异性机制进行差异调节。在这里，我建议对研究项目（K01-DK092355）进行扩展，以更好地评估这两个流行的假设。该提案的总体目标是生成一组小鼠。在细胞特异性 Cre 重组酶破坏后，经典和非经典 NF-κB 信号传导存在缺陷，以更好地表征与具有负调节功能的 NLR 的 NLRP12 调节相关的机制，例如 NLRP12 和非经典 NF-κB 信号传导。 IBD 期间代表了目前尚未充分研究且尚未明确定义的领域。拟议研究产生的小鼠品系和数据将作为未来 R01 提交评估的初步数据。 IBD 背景下这些独特途径的研究代表了一个新的方向，将有助于未来与肠道免疫系统稳态相关的发现，并导致针对这些疾病的新治疗策略。