Impact of ST2 signaling and IBD risk variants on the intestinal epithelium

ST2 信号传导和 IBD 风险变异对肠上皮的影响

• 批准号: 9165525
• 负责人: Michael J Rosen
• 金额: $ 7.8万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9165525
• 关键词: Affect; American; Award; Binding; Cell Differentiation process; Cell Line; Cell physiology; Child; Childhood; Colitis; Colon; Data; Defect; Ensure; Epithelial; Epithelial Cells; Epithelium; Exhibits; Family; Functional disorder; Future; Genes; Genetic; Genetic Variation; Genotype; Goblet Cells; Healed; Homeostasis; Human; In Vitro; Indium; Individual; Inflammation; Inflammatory Bowel Diseases; Interleukin-1; Intestinal Mucosa; Intestines; Knowledge; Laboratories; Letters; Linkage Disequilibrium; Membrane; Molecular Genetics; Mus; Oxazolone; Pathogenesis; Pathway interactions; Patients; Physiological; Prognostic Marker; Proteins; Qualifying; Research; Research Personnel; Risk; Role; Signal Transduction; Single Nucleotide Polymorphism; System; Therapeutic; Tissues; Variant; Work; clinical remission; cytokine; disorder risk; gene function; genetic analysis; healing; intestinal epithelium; member; monolayer; novel therapeutics; protective effect; receptor; research study; response; risk variant; success; tool; two-dimensional

PROJECT SUMMARY Physiologic, molecular, and genetic observations all point to impaired intestinal epithelial function as a key element in the multifactorial pathogenesis of inflammatory bowel disease (IBD). The lack of treatments directed at promoting epithelial homeostasis represents a conspicuous weakness of our current IBD therapeutic armamentarium. Therefore, research is needed that will advance our understanding of mechanisms to preserve epithelial homeostasis in the setting of inflammation. IL-33 is a member of the IL-1 cytokine family that signals through the IL-1 receptor related protein ST2. IL-33 is markedly upregulated in the intestinal mucosa of patients with UC and CD, and single nucleotide polymorphisms (SNPs) in a linkage disequilibrium block containing the gene for ST2 (IL1RL1) are associated with risk for IBD. Genetic deletion of either IL-33 or ST2 results in exacerbation of murine colitis, suggesting a protective effect for IL-33 signaling. While colon epithelial cells express ST2, little is known regarding the direct effects of IL-33 on colon epithelium. Our preliminary data support the hypothesis that IL-33-ST2 signaling in the intestinal epithelium induces goblet cell differentiation and augments barrier function, which is impeded by IBD-associated SNPs within the IL1RL1 locus. In Aim1, we will use primary murine enteroids and two-dimensional monolayers derived from wild type (WT) and ST2–/– mice to determine the direct effects of IL-33-ST2 signaling on colon epithelial cell differentiation and barrier function. In Aim 2, we will use primary colonoid cultures derived from genotyped pediatric IBD and non-IBD patients to determine the effects of IBD-associated SNPs within the IL1RL1 locus on human colon epithelium. This research will elucidate how cytokines preserve or augment epithelial barrier functions in the setting of colitis, and how IBD risk genes impair this response, which may uncover novel therapeutic strategies to preserve and restore epithelial homeostasis in IBD.

项目摘要 生理学、分子学和遗传学的观察结果都指出，肠上皮功能受损是 在炎症性肠病（IBD）的多因素发病机制中的元素。缺乏针对性的治疗 在促进上皮内稳态方面的作用代表了我们目前IBD治疗药物的一个明显弱点， 医疗设备。因此，需要进行研究，以促进我们对机制的理解， 在炎症情况下保持上皮细胞的稳态。IL-33是IL-1细胞因子家族的成员 通过IL-1受体相关蛋白ST 2传递信号。IL-33在肠道中显著上调， UC和CD患者的粘膜，以及连锁不平衡中的单核苷酸多态性（SNP） 含有ST 2基因（IL 1 RL 1）的基因块与IBD的风险相关。IL-33或 ST 2导致鼠结肠炎的恶化，表明对IL-33信号传导的保护作用。而结肠 上皮细胞表达ST 2，关于IL-33对结肠上皮的直接作用知之甚少。我们 初步数据支持肠上皮细胞中IL-33-ST 2信号传导诱导杯状细胞凋亡的假设。 分化和增强屏障功能，这是由IBD相关的SNPs在IL 1 RL 1阻碍 基因座在Aim 1中，我们将使用原代小鼠肠上皮细胞和来自野生型的二维单层细胞， (WT)和ST 2-/-小鼠以确定IL-33-ST 2信号传导对结肠上皮细胞的直接作用。 分化和屏障功能。在目标2中，我们将使用来自基因分型的原代结肠样培养物， 儿童IBD和非IBD患者，以确定IL 1 RL 1基因座内IBD相关SNP的影响 在人类结肠上皮上。这项研究将阐明细胞因子如何保护或增强上皮屏障 在结肠炎的背景下发挥作用，以及IBD风险基因如何损害这种反应，这可能会揭示新的 保护和恢复IBD中上皮稳态的治疗策略。