Basal Progenitor Cells and Eosinophilic Esophagitis

摘要 嗜酸性粒细胞性食管炎 (EoE) 是一种新近出现的疾病，近年来发病率急剧上升 过去十年。它影响所有年龄段的人，尤其是儿童和 30-40 岁的成年人。环氧乙烷 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 改善大多数患者的临床病理特征，但当使用类固醇时，EoE 几乎总是会复发。 已停产。因此，有必要更好地了解这种疾病的病理学，以便得出 新颖有效的治疗方法。我们和其他人之前已经证明 IL-13 在启动过程中发挥着关键作用 EoE 和随后的组织重塑。然而，IL-13调节基础的分子机制 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调查 分析 IL13 刺激的分泌蛋白组，并确定 Tenascin C (TNC250) 的 250kD 亚型是 富含 IL13 处理的人食管基底细胞、小鼠和人 EoE 活检组织。我们的初步数据 进一步表明，敲除编码 TNC250 的转录本会导致基底细胞增殖减少 祖细胞伴有 TNFR 相关因子 (TRAF)3（E3 的一种）水平降低 MAP3K14 泛素连接酶（也称为 NF-kappa-B 诱导激酶 (Nik)）。值得注意的是，删除 Nik 导致 EoE 伴有显着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 表明 Nik 的损失是在食道而不是其他组织（例如胸腺和造血系统）中 对 EoE 发病机制至关重要。我们的假设是 IL-13/TNC250 抑制 Nik 介导的非典型 食管上皮中的 NF-κB 信号传导促进 EoE 发病机制。我们将检验我们的假设 具有以下具体目标：（目标 1）检验 IL-13 下游 TNC250 促进的假设 EoE 发病过程中基底细胞增生。 (目标 2) 确定 Nik 在 EoE 发病机制中的作用， 其中包括两个子目标：（Aim2a）检验食管中 Nik 表达缺失的假设 上皮细胞促进 EoE 发病机制。 (Aim2b) 检验 Nik 损失通过以下方式促进 EoE 的假设： 非规范 NF-kB 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.