Basal Progenitor Cells and Eosinophilic Esophagitis

基底祖细胞和嗜酸性食管炎

基本信息

批准号：
10337314
负责人：
Jianwen Que
金额：
$ 38.81万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10337314
关键词：
Abnormal Cell Address Adult Affect Age Allergens Animal Model Basal Cell Basal Cell Hyperplasia Biopsy Cells Child Chronic Clinic Clinical Coculture Techniques Data Disease Disease Progression Eosinophilic Esophagitis Epithelial Esophageal Stenosis Esophagus Fibrosis Foundations Genetic Goals Hematopoietic System Human Hyperplasia Infiltration Inflammation Inflammatory Integrins Interleukin-13 Interleukin-13 Overexpression Knowledge Lead Liver Lung MAP3K14 gene Mediating Medical Modeling Molecular Mus NF-kappa B Neoplasms Organoids Ovalbumin Pathogenesis Pathway interactions Patients Persons Pharmaceutical Preparations Phase II Clinical Trials Phosphotransferases Play Production Protein Isoforms Proteomics Research Role Signal Transduction Small Interfering RNA Steroids T-Lymphocyte TNF receptor-associated factor 3 Tenascin Testing Thymus Gland Tissues Topical Corticosteroids Transcript Transgenic Organisms Translating Transplantation Tumor Necrosis Factor Receptor Work cytokine design effective therapy eosinophil esophageal squamous cell cancer gain of function humanized antibody immunoreaction improved insight knock-down liver inflammation loss of function mouse model mutant new therapeutic target novel overexpression preference screening stem stem cells ubiquitin-protein ligase

项目摘要

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.

抽象的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，它影响了所有年龄段的人，尤其是 30 岁至 40 岁的成年人。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 在内的长期炎症会导致组织重塑，包括基底祖细胞增生。细胞、上皮下纤维化和食管狭窄，尽管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。因此，有必要更好地了解这种疾病的病理学。我们和其他人之前已经证明 IL-13 在启动中发挥着关键作用。然而，IL-13 调节基础的分子机制。为了解决这个问题，我们最近进行了一项全面的研究。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 活检样本。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 的泛素连接酶（也称为 NF-kappa-B 诱导激酶 (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说明。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）中我们的假设是 IL-13/TNC250 抑制 Nik 介导的非典型现象。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 (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 缺失通过以下方式促进 EoE 的假设。该项目有望提供新的遗传和分子机制。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。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

FOXO1: Another avenue for treating digestive malignancy?

FOXO1：治疗消化道恶性肿瘤的另一种途径？

DOI：
10.1016/j.semcancer.2017.09.009
发表时间：
2018-06
期刊：
Seminars in cancer biology
影响因子：
14.5
作者：
Shi F;Li T;Liu Z;Qu K;Shi C;Li Y;Qin Q;Cheng L;Jin X;Yu T;Di W;Que J;Xia H;She J
通讯作者：
She J

Exclusion of Dlx5/6 expression from the distal-most mandibular arches enables BMP-mediated specification of the distal cap.

从最远端下颌弓排除 Dlx5/6 表达使得 BMP 介导的远端帽规范成为可能。

DOI：
发表时间：
2016
期刊：
影响因子：
11.1
作者：
Vincentz, Joshua W;Casasnovas, Jose J;Barnes, Ralston M;Que, Jianwen;Clouthier, David E;Wang, Jun;Firulli, Anthony B
通讯作者：
Firulli, Anthony B

P63 Deficiency and CDX2 Overexpression Lead to Barrett's-Like Metaplasia in Mouse Esophageal Epithelium.

P63 缺乏和 CDX2 过度表达导致小鼠食管上皮发生 Barrett 样化生。

DOI：
发表时间：
2021-12
期刊：
影响因子：
3.1
作者：
Fang, Yu;Li, Wenbo;Chen, Xiaoxin
通讯作者：
Chen, Xiaoxin

Etiology, cancer stem cells and potential diagnostic biomarkers for esophageal cancer.

食管癌的病因学、癌症干细胞和潜在的诊断生物标志物。

DOI：
10.1016/j.canlet.2019.05.018
发表时间：
2019-08-01
期刊：
Cancer letters
影响因子：
9.7
作者：
Kuancan Liu;T. Zhao;Junkai Wang;Yunyun Chen;Rui Zhang;X. Lan;J. Que
通讯作者：
J. Que

Relationship of the Esophageal Microbiome and Tissue Gene Expression and Links to the Oral Microbiome: A Randomized Clinical Trial.

食管微生物组与组织基因表达的关系以及与口腔微生物组的联系：随机临床试验。

DOI：
发表时间：
2020-12
期刊：
影响因子：
0
作者：
Annavajhala, Medini K;May, Michael;Compres, Griselda;Freedberg, Daniel E;Graham, Roseanna;Stump, Stephania;Que, Jianwen;Korem, Tal;Uhlemann, Anne;Abrams, Julian A
通讯作者：
Abrams, Julian A