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Autophagy and esophageal tissue remodeling in EoE

EoE 中的自噬和食管组织重塑

基本信息

批准号：
9367277
负责人：
Hiroshi Nakagawa
金额：
$ 40.25万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-18 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9367277
关键词：
Adrenal Cortex Hormones Affect Antigens Autophagocytosis Basal Cell Basal Cell Hyperplasia Basic Science Biology CRISPR/Cas technology Cell Lineage Cells Cellular Stress Response Characteristics Chronic Clinical Clinical Data Collagen Coupled Crohn&apos s disease Data Defect Defense Mechanisms Deglutition Deposition Development Diagnosis Diet Disease Disease Progression Down-Regulation Endoscopic Biopsy Eosinophilia Eosinophilic Esophagitis Eosinophilic Infiltrate Epithelial Epithelial Cells Epithelium Esophageal Esophageal Diseases Esophageal Stenosis Esophageal Tissue Esophagitis Event Exposure to Fibroblasts Fibrosis Fluorescence-Activated Cell Sorting Food Gene Expression Profiling Genetic Engineering Growth Homeostasis Human Human Pathology Immune Impairment Infiltration Inflammation Inflammatory Knowledge Laboratories Lamina Propria Mediating Mesenchymal Mission Mitochondria Modeling Molecular Monitor Mus Organoids Oxidative Stress PARK2 gene Pathogenesis Patients Peptic Esophagitis Pharmacology Production Proteins Public Health Publishing Quality of life Radiation Reactive Oxygen Species Regulation Regulator Genes Research Resolution Role Sirolimus Specimen Squamous Epithelium Stratified Squamous Epithelium Structure System TNF gene Testing Therapeutic Tissues Translational Research United States National Institutes of Health Validation cytokine eosinophil food allergen human disease in vivo inflammatory milieu inhibition of autophagy innovation insight keratinocyte mouse model novel novel therapeutics physiologic stressor pre-clinical reconstitution response small hairpin RNA standard of care targeted treatment three dimensional cell culture tissue biomarkers translational impact

项目摘要

PROJECT SUMMARY Eosinophilic esophagitis (EoE) is an emerging antigen-mediated chronic inflammatory disease, characterized by mucosal eosinophilia and tissue remodeling events, leading to basal cell hyperplasia (BCH) and subepithelial fibrosis. While immune cell-mediated mechanisms regulating EoE disease activity are rapidly emerging, our understanding of the relationship between esophageal epithelial biology and EoE pathogenesis is presently limited. Autophagy is a cellular adaptive response to physiologic stressors that is activated in esophageal epithelia upon exposure to EoE inflammation to limit oxidative stress. Pharmacological autophagy inhibition aggravates disease-associated oxidative stress, basal cell hyperplasia (BCH) and eosinophil infiltrates in a robust murine model of EoE, suggesting that autophagy supports esophageal homeostasis via cell autonomous and non-cell autonomous mechanisms in the context of EoE inflammation. The present proposal utilizes murine models with squamous epithelia-specific autophagy impairment coupled with ex vivo esophageal 3D organoids, reconstitute the epithelial-stromal structure in the organotypic 3D culture and EoE patient specimens with associated clinical data as a comprehensive platform to define the mechanistic and functional role of autophagy in EoE pathogenesis. The central hypothesis is that epithelial autophagy is a fundamental mucosal defense mechanism activated to suppress reactive oxygen species-mediated esophageal tissue remodeling in EoE. This hypothesis has been formulated on the basis of strong preliminary data produced in the applicant's laboratory and will be tested by pursuing the following three interrelated Specific Aims: (1) To determine how autophagy influences epithelial cell fate in the EoE inflammatory milieu; (2) To determine the effect of epithelial autophagy on lamina propria remodeling; (3) To evaluate the therapeutic utility of autophagy activation in EoE. These innovative studies will reveal novel insight into the role of autophagy in regulation of epithelial integrity and epithelial-stromal crosstalk in the context of EoE, thereby fundamentally advance the fields of epithelial biology and mucosal defense. By evaluating the therapeutic utility of pharmacological autophagy enhancement in EoE, these studies have the potential for direct translational impact in this disease for which dietary elimination and/or swallowed corticosteroids therapy remain the current standard of care due to a lack of viable targeted therapeutic strategies. Furthermore, this novel therapeutic strategy may serve as a platform for similar approaches in the treatment of esophageal disorders beyond EoE in which BCH and inflammation have been implicated as well as additional human pathologies involving autophagy dysregulation. Thus, this innovative and translational research will have substantial positive impact by integrating basic science and preclinical experimental approaches to define the direct molecular mechanisms underlying esophageal epithelial homeostasis and utilizing this knowledge to direct the development of novel translational applications related to EoE diagnosis, monitoring and therapy.

项目总结