Esophageal tissue aging under homeostatic and inflammatory conditions

稳态和炎症条件下食管组织老化

基本信息

  • 批准号:
    10597646
  • 负责人:
  • 金额:
    $ 44.09万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-06-04 至 2024-03-31
  • 项目状态:
    已结题

项目摘要

Project Summary Esophageal dysfunction and pathology represent significant health burdens in the United States and worldwide. While patient age is an established risk factor for dysphagia, esophageal cancer and Eosinophilic Esophagitis (EoE)-associated subepithelial fibrosis, our understanding of the biology of aging in the esophagus remains elusive. Under homeostatic conditions, esophageal squamous epithelium comprises a basal compartment of proliferative cells that undergo differentiation in suprabasal layers and luminal desquamation, facilitating tissue renewal. Perturbation of this defined proliferation/differentiation gradient in esophageal epithelium is a feature of esophageal pathologies, including EoE. While the prevalence of BCH is nearly identical in pediatric and adult patients with active EoE, preliminary data indicate that BCH is present in ~20% of normal esophageal epithelial specimens from adults while remaining undetectable in normal pediatric specimens. We have recently demonstrated that autophagy (‘self-eating’) is activated in esophageal epithelium in response to EoE inflammation, serving to limit BCH and eosinophilia. Preliminary data indicate that autophagy flux is stalled in aged esophageal epithelium under normal conditions. Moreover, EoE induction in aged mice results in diminished eosinophilia and subepithelial fibrosis. The overarching hypothesis is that age-associated decline in esophageal epithelial autophagy flux impairs tissue homeostasis and contributes to age-associated alterations in EoE phenotype. To test this hypothesis, we will define the functional relationship between mTORC1/autophagy signaling and age-associated esophageal basal cell hyperplasia (Aim 1); elucidate the functional role of epithelial autophagy in age-associated EoE fibrosis (Aim 2); and investigate the role of epithelial autophagy in the EoE inflammatory response in the context of aging (Am 3). The biology of aging in the esophagus represents a significant knowledge gap as understanding mechanisms of tissue aging has the potential to improve strategies for diagnosis, monitoring and therapy of widely prevalent esophageal diseases, including EoE and cancer. Here, we investigate epithelial autophagy as a novel regulator of aging in the esophagus under conditions of homeostasis and EoE inflammation using an innovative approach coupling functional evaluation of human endoscopic biopsies, 3D esophageal organoids and a murine model of EoE featuring age-associated fibrosis. These studies have great potential to provide novel insight into age-relevant mechanisms/cellular phenotypes in the esophagus and unveil new biomarkers and therapeutic targets for EoE and other age-associated disorders affecting the esophagus.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Kelly A Whelan其他文献

Kelly A Whelan的其他文献

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{{ truncateString('Kelly A Whelan', 18)}}的其他基金

The impact of exposure to allergic inflammation on esophageal carcinogenesis
接触过敏性炎症对食管癌发生的影响
  • 批准号:
    10308094
  • 财政年份:
    2020
  • 资助金额:
    $ 44.09万
  • 项目类别:
The impact of exposure to allergic inflammation on esophageal carcinogenesis
接触过敏性炎症对食管癌发生的影响
  • 批准号:
    10112399
  • 财政年份:
    2020
  • 资助金额:
    $ 44.09万
  • 项目类别:
A pilot study to define maintained alterations in mitochondrial DNA of eosinophilic esophagitis patients that may be exploited clinically
一项初步研究,旨在确定嗜酸性食管炎患者线粒体 DNA 的持续改变,并可在临床上加以利用
  • 批准号:
    10308684
  • 财政年份:
    2020
  • 资助金额:
    $ 44.09万
  • 项目类别:
Esophageal tissue aging under homeostatic and inflammatory conditions
稳态和炎症条件下食管组织老化
  • 批准号:
    10559923
  • 财政年份:
    2019
  • 资助金额:
    $ 44.09万
  • 项目类别:
Esophageal tissue aging under homeostatic and inflammatory conditions
稳态和炎症条件下食管组织老化
  • 批准号:
    10731168
  • 财政年份:
    2019
  • 资助金额:
    $ 44.09万
  • 项目类别:
Investigating the role of mitochondria in Eosinophilic Esophagitis pathogenesis.
研究线粒体在嗜酸性食管炎发病机制中的作用。
  • 批准号:
    10516513
  • 财政年份:
    2019
  • 资助金额:
    $ 44.09万
  • 项目类别:
Esophageal tissue aging under homeostatic and inflammatory conditions
稳态和炎症条件下食管组织老化
  • 批准号:
    10379344
  • 财政年份:
    2019
  • 资助金额:
    $ 44.09万
  • 项目类别:
Autophagy regulation of esophageal basal cell dynamics
自噬调节食管基底细胞动力学
  • 批准号:
    9586311
  • 财政年份:
    2018
  • 资助金额:
    $ 44.09万
  • 项目类别:
Role of Notch 1 signaling in esophageal carcinogenesis
Notch 1信号在食管癌发生中的作用
  • 批准号:
    8774834
  • 财政年份:
    2013
  • 资助金额:
    $ 44.09万
  • 项目类别:
Role of Notch 1 signaling in esophageal carcinogenesis
Notch 1信号在食管癌发生中的作用
  • 批准号:
    8827716
  • 财政年份:
    2013
  • 资助金额:
    $ 44.09万
  • 项目类别:

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