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:
  • 金额:
    $ 40.25万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(0)
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Hiroshi Nakagawa其他文献

Hiroshi Nakagawa的其他文献

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{{ truncateString('Hiroshi Nakagawa', 18)}}的其他基金

The Organoid and Cell Culture Core
类器官和细胞培养核心
  • 批准号:
    10443137
  • 财政年份:
    2022
  • 资助金额:
    $ 40.25万
  • 项目类别:
The Organoid and Cell Culture Core
类器官和细胞培养核心
  • 批准号:
    10612964
  • 财政年份:
    2022
  • 资助金额:
    $ 40.25万
  • 项目类别:
Aldh2 and mitochondrial homeostasis in esophageal pathobiology
食管病理学中的 Aldh2 和线粒体稳态
  • 批准号:
    10159805
  • 财政年份:
    2019
  • 资助金额:
    $ 40.25万
  • 项目类别:
Aldh2 and mitochondrial homeostasis in esophageal pathobiology
食管病理学中的 Aldh2 和线粒体稳态
  • 批准号:
    9897450
  • 财政年份:
    2019
  • 资助金额:
    $ 40.25万
  • 项目类别:
Aldh2 and mitochondrial homeostasis in esophageal pathobiology
食管病理学中的 Aldh2 和线粒体稳态
  • 批准号:
    10383155
  • 财政年份:
    2019
  • 资助金额:
    $ 40.25万
  • 项目类别:
Autophagy and esophageal tissue remodeling in EoE
EoE 中的自噬和食管组织重塑
  • 批准号:
    10298488
  • 财政年份:
    2017
  • 资助金额:
    $ 40.25万
  • 项目类别:
Autophagy and esophageal tissue remodeling in EoE
EoE 中的自噬和食管组织重塑
  • 批准号:
    10463814
  • 财政年份:
    2017
  • 资助金额:
    $ 40.25万
  • 项目类别:
Autophagy and esophageal tissue remodeling in EoE
EoE 中的自噬和食管组织重塑
  • 批准号:
    10615142
  • 财政年份:
    2017
  • 资助金额:
    $ 40.25万
  • 项目类别:
Integrative mouse pathobiology: GI epithelial biology and genetics
综合小鼠病理学:胃肠道上皮生物学和遗传学
  • 批准号:
    8690996
  • 财政年份:
    2011
  • 资助金额:
    $ 40.25万
  • 项目类别:
Integrative mouse pathobiology: GI epithelial biology and genetics
综合小鼠病理学:胃肠道上皮生物学和遗传学
  • 批准号:
    8226085
  • 财政年份:
    2011
  • 资助金额:
    $ 40.25万
  • 项目类别:

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