Ulcerative Colitis - Regulation of the IL-13 Receptor System

溃疡性结肠炎 - IL-13 受体系统的调节

• 批准号: 8875675
• 负责人: Peter Mannon
• 金额: $ 29.4万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8875675
• 关键词: Acute; Affect; Aftercare; Apoptosis; Biopsy; CCL4 gene; Cells; Clinic; Clinical; Clinical Trials Design; Colitis; Crohn' s disease; Data; Development; Disease; Disease remission; Employee Strikes; Eosinophilic Esophagitis; Epithelial; Epithelial Cells; Epithelium; Extrinsic asthma; Gene Expression; Gene Expression Profile; Genes; Goals; Health; Helminths; Heterogeneity; Human; IL13Ralpha2; IL4R gene; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Injury; Interferon-beta; Interleukin-13; Intestines; Knowledge; Lamina Propria; Lead; Ligands; Lymphoid Cell; Measures; Mediating; Methods; Monitor; Mononuclear; Mus; Outcome; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Play; Population; Production; Proteins; Receptor Signaling; Regulation; Role; Signal Pathway; Signal Transduction; Site; Source; Specific qualifier value; Staging; Stimulus; System; Testing; Tight Junctions; Tissues; Toxic effect; Ulcerative Colitis; Up-Regulation; Work; active control; adaptive immunity; base; cytokine; design; disorder control; drug testing; glycosylation; improved; innovation; interleukin-13 receptor; mouse model; new therapeutic target; novel; receptor; receptor expression; receptor function; response; success; targeted treatment; therapeutic target; transcriptome sequencing

DESCRIPTION (provided by applicant): Dysregulation of IL-13 and the IL-13 receptor pathway is the most defining cytokine abnormality of ulcerative colitis (UC). The significance of this finding is established not only by the observed toxicity exerted by IL-13 on the colonic epithelium in vitro and the successful treatment of murine oxazalone colitis by anti-IL-13 strategies, but also by results of a recent trial of interferon-beta in UC that showed significant post-treatment decreases in IL-13 production that were restricted to the clinical responders. Because multiple novel therapies targeting IL-13 activity at various points in the ligand-receptor-signaling pathway are currently in development, identifying the predominant mechanism of dysregulation of the IL-13 receptor system in UC will lead to optimized clinical trial design through choice of agent and monitoring for effect. The preliminary data for this proposal show striking upregulation of the decoy IL13Ralpha2 receptor in the epithelium and excess production of IL-13 by lamina propria mononuclear cells in many, but not all, active ulcerative colitis patients and are absent in healthy controls and active Crohn's disease. These findings provide the innovation for new and critical questions about UC: is the epithelial IL13Ra2 expression protective or injurious in active UC, is the heterogeneity of IL-13 production related to NKT versus innate lymphoid cell production, and are there IL-13 expression-based endotypes of UC that can predict response to IL-13-targeted therapies? Using primary gut tissue, methods to measure regulation of receptor expression, IL-13 signaling and receptor activity, and phenotypes of the cells producing IL-13 and expressing IL-13 receptors will allow comparison between subsets of UC patients, Crohn's and healthy controls. These studies will define the relevant cell source of IL-13 in UC, the regulation of its production and the sites and mechanisms of action among and within different strata of UC disease activity. The results will be applicable to other mucosal inflammatory diseases like allergic asthma and eosinophilic esophagitis where IL-13 also drives disease and new therapies targeting IL-13 are needed.

描述（由申请人提供）：IL-13 和 IL-13 受体途径的失调是溃疡性结肠炎 (UC) 最明显的细胞因子异常。这一发现的意义不仅在于观察到IL-13在体外对结肠上皮产生的毒性以及通过抗IL-13策略成功治疗小鼠恶唑酮结肠炎，而且还在于最近一项干扰素-β治疗UC的试验结果表明，治疗后IL-13的产生显着下降，而这种下降仅限于临床反应者。由于目前正在开发多种针对配体-受体-信号通路中不同点的 IL-13 活性的新型疗法，因此确定 UC 中 IL-13 受体系统失调的主要机制将通过选择药物和监测效果来优化临床试验设计。 该提案的初步数据显示，在许多（但不是全部）活动性溃疡性结肠炎患者中，上皮中的诱饵 IL13Ralpha2 受体显着上调，固有层单核细胞过度产生 IL-13，而在健康对照和活动性克罗恩病中则不存在。这些发现为有关 UC 的新的关键问题提供了创新：上​​皮 IL13Ra2 表达在活动性 UC 中是保护性的还是有害的，IL-13 产生的异质性是否与 NKT 与先天淋巴细胞产生相关，以及基于 IL-13 表达的 UC 内型是否可以预测对 IL-13 靶向治疗的反应？使用原代肠道组织，测量受体表达调节、IL-13 信号传导和受体活性以及产生 IL-13 和表达 IL-13 受体的细胞表型的方法将允许在 UC 患者、克罗恩病和健康对照的子集之间进行比较。这些研究将确定 UC 中 IL-13 的相关细胞来源、其产生的调节以及 UC 疾病活动不同层次之间和内部的作用位点和机制。该结果将适用于其他粘膜炎症性疾病，如过敏性哮喘和嗜酸粒细胞性食管炎，这些疾病也由 IL-13 驱动，因此需要针对 IL-13 的新疗法。