Autophagy and esophageal tissue remodeling in EoE

EoE 中的自噬和食管组织重塑

• 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
• 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' 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

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 嗜酸性食管炎(EoE)是一种新出现的抗原介导的慢性炎症性疾病，其特征是 通过粘膜嗜酸性粒细胞增多和组织重塑事件，导致基底细胞增生(BCH)和 上皮下纤维化。而免疫细胞介导的调节EoE疾病活动的机制正在迅速 食道上皮生物学与食管炎发病关系的新认识 目前是有限的。自噬是一种细胞对生理应激源的适应性反应，在 暴露于EoE炎症时的食道上皮细胞，以限制氧化应激。药理自噬 抑制加重疾病相关的氧化应激、基底细胞增生(BCH)和嗜酸性粒细胞 在强健的EoE小鼠模型中渗透，提示自噬通过以下途径支持食道内稳态 EoE炎症背景下的细胞自主和非细胞自主机制。现在 建议利用扁平上皮细胞特异性自噬损伤的小鼠模型结合体外实验 食道3D器质，在器质性3D培养和EoE中重建上皮-间质结构 患者标本和相关的临床数据作为一个全面的平台来定义机制和 自噬在EoE发病机制中的作用。中心假设是上皮细胞自噬是一种 激活基本的粘膜防御机制以抑制活性氧介导的 EoE中的食道组织重塑。这一假设是在强有力的初步假设的基础上提出的 在申请人的实验室中产生的数据，将通过以下三个相互关联的方式进行测试 具体目的：(1)确定自噬如何影响EoE炎症环境中上皮细胞的命运； (2)确定上皮自噬对固有层重塑的影响；(3)评价自噬对固有层重塑的影响。 自噬激活在EoE中的治疗作用。这些创新的研究将揭示对这一角色的新见解 在EoE的背景下，自噬在调节上皮完整性和上皮-间质串扰中的作用，从而 从根本上推进上皮生物学和粘膜防御领域。通过评估治疗性 药物自噬增强在EOE中的应用，这些研究有可能直接 饮食消除和/或吞服皮质类固醇治疗对这种疾病的翻译影响 由于缺乏可行的有针对性的治疗战略，目前的护理标准仍然存在。此外，这一点 新的治疗策略可以为类似的食道治疗方法提供一个平台 与BCH和炎症有关的EoE以外的疾病以及额外的人类 涉及自噬失调的病理学。因此，这种创新性和转化性的研究将具有 通过整合基础科学和临床前实验方法来定义 食道上皮动态平衡的直接分子机制和利用这一知识 指导与EoE诊断、监测和治疗相关的新型翻译应用程序的开发。