Basal Progenitor Cells and Eosinophilic Esophagitis

摘要 嗜酸性食管炎(EoE)是一种最近表征的疾病，在过去的几年里一直在急剧上升 过去十年。它影响到所有年龄段的人，特别是30-40岁的儿童和成年人。S 致病机制与过敏原/免疫反应和高水平的细胞因子有关 包括IL-13。长期炎症导致组织重塑，包括基底前体细胞增殖 细胞、上皮下纤维化和食道狭窄。虽然常见的局部皮质类固醇治疗 改善了大多数患者的临床病理特征，当类固醇治疗时，EOE几乎总是复发 停产。因此，对这种疾病的病理生物学有更好的了解是必要的。 新的有效治疗方法。我们和其他人之前已经证明，IL-13在启动过程中起关键作用 EoE和随后的组织重塑。然而，IL-13调节碱性磷酸酶的分子机制 祖细胞在很大程度上仍未被探索。为了解决这个问题，我们最近进行了一次全面的 对IL13刺激的分泌体进行分析，确定Tenascin C(TNC250)的250kD异构体是 富含IL13处理的人食道基底细胞、小鼠和人的EoE活检组织。我们的初步数据 进一步表明，下调编码TNC250的转录本导致基底细胞增殖减少 祖细胞伴随着TNFR相关因子(TRAF)3水平的降低，这是一种E3 MAP3K14的泛素连接酶(也称为核因子-kappa-B诱导激酶(NIK))。值得注意的是，Nik的删除 导致EoE，伴有明显的基底细胞增生和嗜酸性粒细胞浸润。我们的初步数据进一步 提示在食道而不是其他组织(如胸腺和造血系统)中Nik的丢失是 对EoE的发病至关重要。我们的假设是IL-13/TNC250抑制NIK介导的非正则效应 食道上皮中的核因子-κB信号转导促进EoE的发生。我们将检验我们的假设 具体目标如下：(Aim1)检验IL-13下游的TNC250促进 EoE发病过程中的基底细胞增生。(AIM2)为确定Nik在EoE发病机制中的作用， 它包括两个子目标：(Aim2a)检验NIK在食道中表达缺失的假设 上皮细胞促进EoE的发病。(Aim2b)验证Nik通过以下途径促进EoE的假设 非典型的核因子-kB信号转导。该项目有望提供新的遗传和分子机制。 调节基础祖细胞。在EoE动物模型中研究核因子-kB信号的启示 将为将这些发现转化为临床奠定重要的基础。

ABSTRACT Eosinophilic esophagitis (EoE) is a recently characterized disease that has been rising dramatically over the past decade. It affects people of all ages with a preference in children and adults in their 30-40’s. EoE pathogenesis has been associated with allergen/immune reactions with characterized high levels of cytokines including IL-13. Prolonged inflammation results in tissue remodeling including hyperplasia of basal progenitor cells, subepithelial fibrosis and stricture of the esophagus. Although common topical corticosteroid therapy improves the clinicopathologic features in most patients, EoE almost always recurs when steroids are discontinued. Therefore, a better understanding of the pathobiology of this disease is necessitated for deriving novel effective treatment. We and others have previously shown that IL-13 plays a critical role in the initiation of EoE and subsequent tissue remodeling. However, the molecular mechanism by which IL-13 regulates basal progenitor cells remains largely unexplored. To address this issue we recently performed a comprehensive analysis of IL13-stimulated secretome, and identified that the 250kD isoform of Tenascin C (TNC250) is enriched in IL13-treated human esophageal basal cells, mouse and human EoE biopsies. Our preliminary data further show that knockdown of the transcripts encoding TNC250 leads to reduced proliferation of basal progenitor cells accompanied by decreased levels of TNFR-associated factors (TRAF)3 which is an E3 ubiquitin Ligase for MAP3K14 (also known as NF-kappa-B-inducing kinase (Nik)). Significantly, deletion of Nik leads to EoE with prominent basal cell hyperplasia and eosinophil infiltration. Our preliminary data further suggest that loss of Nik in the esophagus but not other tissues (e.g. thymus and hematopoietic system) is critical for EoE pathogenesis. Our hypothesis is that IL-13/TNC250 inhibits Nik-mediated non-canonical NF-κB signaling in the esophageal epithelium to promote EoE pathogenesis. We will test our hypothesis with the following specific aims: (Aim1) To test the hypothesis that TNC250 downstream of IL-13 promotes basal cell hyperplasia during EoE pathogenesis. (Aim2) To determine the role of Nik in EoE pathogenesis, which include two subaims: (Aim2a) To test the hypothesis that loss of Nik expression in the esophageal epithelium promotes EoE pathogenesis. (Aim2b) To test the hypothesis that loss of Nik promotes EoE through non-canonical NF-kB signaling. This project is expected to provide novel genetic and molecular mechanisms regulating basal progenitor cells. The insights gained through studying NF-kB signaling in EoE animal models will lay an important foundation for translating these findings into the clinic.