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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：
10298488
负责人：
Hiroshi Nakagawa
金额：
$ 48.21万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-18 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298488
关键词：
3-Dimensional Affect Antioxidants Autophagocytosis Basal Cell Basal Cell Hyperplasia Biology Biopsy CRISPR/Cas technology Cell Fate Control Cell Lineage Cells Cellular Stress Response Cellular biology Chronic Clinical Clonal Expansion Coupled Data Defect Defense Mechanisms Desmosomes Development Disease Dose Down-Regulation Drug Targeting Eosinophilic Esophagitis Epithelial Esophageal Diseases Esophageal Stenosis Esophageal Tissue Esophagitis Esophagus Event Fibrosis Flow Cytometry Genetic Genetically Engineered Mouse Growth Homeostasis Human Immune Impairment Infiltration Inflammation Inflammatory Interleukin-13 Knowledge Label Laboratories Lamina Propria Link Mediating Mediator of activation protein Microscopy Mission Mitochondria Mitochondrial DNA Mitotic Modeling Mucous Membrane Mus Nature Organoids Oxidative Stress Pathogenesis Patients Peptic Esophagitis Pharmacology Proteins Public Health Publications Quality of life Radiation Reactive Oxygen Species Research Role Signal Transduction Squamous Epithelium Stratified Squamous Epithelium Structure Tamoxifen Testing Tight Junctions Tissues United States National Institutes of Health Validation base cytokine drug testing experimental study food allergen human disease inflammatory milieu innovation insight keratinocyte mitochondrial autophagy mouse model notch protein novel self-renewal stress reactivity

项目摘要

Project summary Esophageal stratified squamous epithelia comprise proliferative basal cells that undergo terminal differentiation in the suprabasal cell layer. This homeostatic proliferation-differentiation gradient is regulated by Notch signaling that is impaired in eosinophilic esophagitis (EoE), a chronic inflammatory disorder characterized by mucosal eosinophilic infiltration, basal cell hyperplasia (BCH) and subepithelial fibrosis. BCH contributes to a barrier defect that facilitates lamina propria remodeling, culminating in fibrotic esophageal strictures that severely affect patients’ quality of life. While food allergen-activated immune cells and cytokines mediate EoE pathogenesis, the relationship between esophageal epithelial biology and EoE pathogenesis remains elusive. The ongoing project (R01-114436) has established the role of autophagy, a highly conserved cellular stress response, as a fundamental mucosal defense mechanism in EoE. Epithelial autophagy activation involves mitochondrial stress and reactive oxygen species (ROS) induced by proinflammatory EoE-relevant cytokines such as IL-13, which in turn stimulate BCH. BCH features depletion of CD73+ basal cells and reciprocal expansion of CD73- cells with low Notch activity, thereby limiting terminal differentiation. IL-13 promotes BCH by inhibiting Notch while inducing ROS-mediated mitochondrial (mt) damage marked by mtDNA depletion. Moreover, CD73- cells may maintain BCH via Notch-independent epithelial renewal. The overall objective in this competing renewal application is to elucidate the nature of basal cell fate regulation in EoE pathogenesis. The central hypothesis is that EoE-related inflammation influences basal cells’ activity to promote esophageal tissue remodeling. This hypothesis has been formulated based upon strong preliminary data and publications from the applicant’s laboratory and will be pursued through the following interrelated Specific Aims: (1) To elucidate how autophagy activation limits BCH in the EoE inflammatory milieu; (2) To delineate the role of mitochondrial damage in EoE-related BCH; (3) To unravel how Notch signaling protects against tissue remodeling in EoE. The present proposal utilizes a robust murine model of EoE with squamous epithelia- specific autophagy impairment, mtDNA depletion, or Notch inhibition with concurrent basal cell lineage tracing. These approaches are coupled with ex vivo esophageal 3D organoids from EoE mice and patient biopsies to define the mechanistic and functional role of autophagy and mitochondria in basal cell homeostasis. These innovative studies will reveal novel insights into esophageal basal cell biology and tissue remodeling. With genetically engineered mice, 3D organoids and patient biopsies, we will build a comprehensive platform for the development and validation of novel translational applications related to EoE therapy (autophagy activation and mitochondria-targeted antioxidants). These findings may have direct clinical impact in EoE, and potentially other diseases (e.g. GERD) where autophagy, epithelial barrier defects and fibrosis have been implicated.

项目总结