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

项目总结 生理学、分子和遗传学观察都表明肠上皮功能受损是关键 炎症性肠病(IBD)的多因素致病因素。缺乏针对性的治疗 在促进上皮细胞动态平衡方面，这是我们目前IBD治疗的一个明显弱点 兵工厂。因此，需要进行研究，以促进我们对机制的理解 在炎症的背景下保持上皮的动态平衡。IL-33是IL-1细胞因子家族的成员 它通过IL-1受体相关蛋白ST2发出信号。IL-33在肠道中显著上调 UC和CD患者粘膜与连锁不平衡的单核苷酸多态(SNPs) 含有ST2基因的阻断(IL1RL1)与IBD的风险相关。IL-33或IL-33的基因缺失 ST2导致小鼠结肠炎加重，提示对IL-33信号有保护作用。While冒号 上皮细胞表达ST2，但IL-33对结肠上皮细胞的直接作用知之甚少。我们的 初步数据支持肠上皮细胞中IL-33-ST2信号诱导杯状细胞的假说 分化和增强屏障功能，这是由IL1RL1中与IBD相关的SNP所阻碍的 轨迹。在Aim1中，我们将使用原代小鼠肠样和来自野生型的二维单分子层 (WT)和ST2-/-小鼠研究IL-33-ST2信号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癌培养物 儿童IBD和非IBD患者IL1RL1基因座中与IBD相关的SNPs的研究 在人类结肠上皮细胞上。这项研究将阐明细胞因子如何保护或增强上皮屏障。 在结肠炎环境中的作用，以及IBD风险基因如何损害这种反应，这可能会发现新的 保护和恢复IBD上皮内环境平衡的治疗策略。

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.