Ulcerative Colitis - Regulation of the IL-13 Receptor System

溃疡性结肠炎 - IL-13 受体系统的调节

基本信息

批准号：
8706859
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
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8706859
关键词：
Acute Affect Aftercare Apoptosis Biopsy CCL4 gene Cells Clinic Clinical Clinical Trials Design Colitis Crohn&apos s disease Data Development Disease Disease remission Employee Strikes Eosinophilic Esophagitis Epithelial Epithelial Cells Epithelium Extrinsic asthma Gene Expression Gene Expression Profile Genes Goals Helminths Heterogeneity Human IL13Ralpha2 IL4R gene Immune response 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 base cytokine design disorder control drug testing glycosylation improved innovation interleukin-13 receptor mouse model new therapeutic target novel public health relevance receptor receptor expression receptor function response success therapeutic target transcriptome sequencing

项目摘要

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）最具定义的细胞因子异常。 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.由于目前正在开发配体信号途径的多种新型疗法，该疗法靶向IL-13活性，在UC中确定IL-13受体系统失调的主要机制，将通过选择试剂和监测效果来实现优化的临床试验设计。该提案的初步数据表明，在许多但并非全部活跃的溃疡性结肠炎患者中，诱饵IL13RALPHA2受体的上调以及在健康对照组中缺乏主动性溃疡性结肠炎患者的lamina Propia单核细胞对IL-13的过量上调。这些发现为有关UC的新的关键问题提供了创新：在活跃UC中，上皮IL13RA2表达或有害的是IL-13产量的异质性，与NKT相对于先天淋巴样细胞的产生而言，以及IL-13表达的基于IL-13表达的内型，并且可以预测对IL-13 TertargetEd therget therget therget的响应吗？使用原发性肠道组织，测量受体表达，IL-13信号传导和受体活性的调节方法，以及产生IL-13和表达IL-13受体的细胞的表型，将允许在UC患者，Crohn和健康对照的子集之间进行比较。这些研究将定义UC中IL-13的相关细胞来源，其生产的调节及其在UC疾病活性不同阶层之间和内部的作用位置和作用机理。结果将适用于其他粘膜炎症性疾病，例如过敏性哮喘和嗜酸性食管炎，其中IL-13还需要驱动疾病，并且需要针对IL-13的新疗法。