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（由适用提供）：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，全球超过400万人。我们实验室的先前工作已经确定了来自NLR的模式识别受体家族的新型细胞蛋白，该家族在IBD期间的炎症和肿瘤发育负面调节。我们先前已经表明，NLR NLRP12是实验性结肠炎和感染驱动的肿瘤发生的潜在调节剂。在IBD期间，NLRP12通过衰减规范或非纳尔纳尔NF-κB信号传导调节胃肠道注射。虽然在IBD期间的规范NF-κB信号通路的作用已经很好地确定，但非典型的NF-κB级联反应的贡献相对未表征。我们以前的发现表明，在没有NLRP12的情况下，一对与非典型NF-κB信号相关的趋化因子显着上调，并且与小鼠IBD病理生物学增加有关。这些相同的趋化因子在人IBD患者中也失调。例如，我们的初步数据表明，在CD和UC患者中，NLRP12调节的趋化因子CXCL13分别上调了42倍和23倍，分别对英夫利昔单抗无反应。总之，这些数据说明了IBD期间NLRP12和非典型的NF-κB信号的重要性。但是，基本机制仍未解决。一种假设表明，NLRP12在IBD期间减弱了规范的NF-κB信号。而我们的初步数据支持的第二个假设表明NLRP12抑制了非cancial nf-κB信号传导级联。假设机制中的明显差异可以通过考虑规范的NF-κB途径可以显着影响非全面的NF-κB信号传导来核对。同样，这些途径可能会通过细胞类型和/或临时特定机制进行不同的调节，从而显着影响IBD发病机理。在这里，我提出了研究项目的扩展（K01-DK092355），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，这些小鼠在细胞特异性CRE-结构酶破坏后在规范和非典型的NF-κB信号传导中具有确定性，以更好地表征与IBD的NLRP12调制相关的机制。 IBD期间具有负调控功能的NLR，例如NLRP12和非典型的NF-κB信号传导，代表了目前已被理解且不定义的区域。拟议研究产生的小鼠线和数据将作为未来R01提交的初步数据。在IBD背景下对这些独特途径的评估代表了一个新的方向，将有助于与肠道中与免疫系统稳态相关的未来发现，并导致针对这些疾病的新治疗策略。