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: 9298635
• 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/9298635
• 关键词: Affect; American; Award; B cell differentiation; Cell Differentiation process; Cell Line; Cell physiology; Child; Childhood; Colitis; Colon; Data; Defect; Elements; Ensure; Epithelial; Epithelial Cells; Epithelium; Exhibits; Family; Functional disorder; Future; Genes; Genetic; Genetic Variation; Genotype; Goblet Cells; Homeostasis; Human; Impairment; In Vitro; Individual; Inflammation; Inflammatory Bowel Diseases; Interleukin-1; Interleukin-1 Receptors; Intestinal Mucosa; Intestines; Knowledge; Laboratories; Letters; Linkage Disequilibrium; Membrane; Molecular Genetics; Mus; Oxazolone; Pathogenesis; Pathway interactions; Patients; Physiological; Prognostic Marker; Proteins; Research; Research Personnel; Risk; Role; Signal Transduction; Single Nucleotide Polymorphism; System; Therapeutic; Tissues; Variant; Work; clinical remission; cytokine; experimental study; genetic analysis; healing; intestinal epithelium; member; monolayer; novel therapeutics; protective effect; receptor; 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，分子和遗传观察均应损害肠上皮功能作为钥匙 炎症性肠病（IBD）多因素发病机理的元素。缺乏治疗的指导 促进上皮稳态代表了我们当前的IBD疗法的明显弱点 武术。因此，需要进行研究，以提高我们对机制的理解 在炎症的情况下保留上皮稳态。 IL-33是IL-1细胞因子家族的成员 通过IL-1受体相关蛋白ST2发出信号。 IL-33在肠中明显更新 连锁二动型中的UC和CD患者的粘膜以及单核苷酸多态性（SNP） 含有ST2基因的块（IL1RL1）与IBD风险有关。 IL-33或 ST2导致鼠结肠炎加剧，这表明IL-33信号的受保护作用。而结肠 上皮细胞表达ST2，关于IL-33对结肠上皮的直接影响知之甚少。我们的 初步数据支持以下假设：肠上皮中的IL-33-ST2信号传导诱导杯状细胞 分化和增强屏障功能，这受到IBD相关的IL1RL1中的SNP的阻碍 轨迹。在AIM1中，我们将使用源自野生型的主要鼠肠和二维单层 （WT）和ST2 - / - 小鼠确定IL-33-ST2信号对结肠上皮细胞的直接影响 分化和屏障功能。在AIM 2中，我们将使用源自基因分型的原代结肠培养物 小儿IBD和非IBD患者确定IBD相关SNP在IL1RL1基因座中的影响 关于人类结肠上皮。这项研究将阐明细胞因子如何保存或增大上皮屏障 在结肠炎的环境中的功能以及IBD风险基因如何损害这种反应，这可能会发现新颖 在IBD中保存和恢复上皮稳态的治疗策略。