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.

项目摘要嗜酸性食管炎（EOE）是一种新兴的抗原介导的慢性炎性疾病，其特征是通过粘膜嗜酸性粒细胞和组织重塑事件，导致基底细胞增生（BCH）和上皮下纤维化。而调节EOE疾病活性的免疫细胞介导的机制迅速新兴，我们对食道上皮生物学与EOE发病机理之间关系的理解目前有限。自噬是对生理胁迫源的细胞自适应反应，该反应被激活暴露于EOE炎症时，食管上皮症限制氧化应激。药理自噬抑制加剧疾病相关的氧化应激，基底细胞增生（BCH）和嗜酸性粒细胞在强大的EOE鼠模型中浸润，表明自噬支持食管稳态在EOE炎症的背景下，细胞自主和非细胞自主机制。现在提案利用带有鳞状上皮特异性自噬损伤的鼠模型与Ex Vivo相结合食道3D器官，重建器官3D培养和EOE中的上皮核结构具有相关临床数据的患者标本是定义机械和的综合平台自噬在EOE发病机理中的功能作用。中心假设是上皮自噬是一个激活以抑制活性氧介导的基本粘膜防御机制 EOE中的食管组织重塑。该假设是根据强大的初步提出的申请人实验室中产生的数据，将通过追求以下三个相互关联来测试具体目的：（1）确定自噬如何影响EOE炎症环境中的上皮细胞命运；（2）确定上皮自噬对固有层的重塑的影响；（3）评估 EOE自噬激活的治疗效用。这些创新的研究将揭示有关该角色的新见解在EOE的背景下，自噬调节上皮完整性和上皮 - 层串扰从根本上推进了上皮生物学和粘膜防御的领域。通过评估治疗 EOE中药理学自噬增强的实用性，这些研究可能直接饮食中消除和/或吞咽皮质类固醇治疗的转化影响由于缺乏有针对性的治疗策略，因此仍然是当前护理标准。此外，这个新颖的治疗策略可以作为食管治疗类似方法的平台涉及BCH和炎症的EOE之外的疾病以及其他人类涉及自噬失调的病理。因此，这项创新和转化研究将有通过整合基础科学和临床前实验方法来定义实质性积极影响食管上皮稳态的直接分子机制，并利用这些知识指导与EOE诊断，监测和治疗有关的新型翻译应用的发展。