Basal Progenitor Cells and Eosinophilic Esophagitis

摘要 嗜酸性粒细胞性食管炎（EoE）是一种最近的特征性疾病， 过去十年它影响所有年龄段的人，尤其是30-40岁的儿童和成人。EOE 发病机制与具有高水平细胞因子特征的过敏原/免疫反应有关 包括IL-13。长期炎症导致组织重塑，包括基底祖细胞增生 细胞，上皮下纤维化和食管狭窄。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 停止了。因此，有必要更好地了解这种疾病的病理生物学，以获得 新的有效治疗。我们和其他人先前已经表明，IL-13在启动中起着关键作用， 以及随后的组织重塑然而，IL-13调节基础胰岛素分泌的分子机制， 祖细胞仍然在很大程度上未被探索。为了解决这个问题，我们最近进行了一次全面的 IL 13刺激的分泌组的分析，并确定了250 kD的腱生蛋白C（TNC 250）亚型是 在IL 13处理的人食管基底细胞、小鼠和人EoE活组织检查中富集。我们的初步数据 进一步表明编码TNC 250的转录本的敲除导致基底细胞增殖减少 祖细胞伴随TNFR相关因子（TRAF）3水平降低，TRAF 3是E3 MAP 3 K14的泛素连接酶（也称为NF-κ-B诱导激酶（Nik））。值得注意的是，Nik的缺失 导致EoE伴显著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 提示食管中Nik而不是其他组织（如胸腺和造血系统）的丢失是 对EoE发病机制至关重要。我们的假设是IL-13/TNC 250抑制了NIK介导的非典型细胞凋亡。 食管上皮中NF-κB信号通路促进EoE发病。我们将测试我们的假设 （目的1）检验IL-13下游的TNC 250促进IL-13表达的假设， EoE发病过程中基底细胞增生。（目的2）为了确定Nik在EoE发病机制中的作用， 其包括两个子目的：（Aim 2a）为了检验食管中Nik表达的缺失与食管癌的发生有关的假设， 上皮促进EoE发病。（目标2b）为了检验Nik缺失通过以下途径促进EoE的假设： 非典型NF-κ B信号传导。该项目有望提供新的遗传和分子机制 调节基底祖细胞。通过研究EoE动物模型中的NF-kB信号传导获得的见解 将为将这些发现转化为临床奠定重要基础。

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.