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:
- 金额:$ 48.21万
- 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 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAffectAntioxidantsAutophagocytosisBasal CellBasal Cell HyperplasiaBiologyBiopsyCRISPR/Cas technologyCell Fate ControlCell LineageCellsCellular Stress ResponseCellular biologyChronicClinicalClonal ExpansionCoupledDataDefectDefense MechanismsDesmosomesDevelopmentDiseaseDoseDown-RegulationDrug TargetingEosinophilic EsophagitisEpithelialEsophageal DiseasesEsophageal StenosisEsophageal TissueEsophagitisEsophagusEventFibrosisFlow CytometryGeneticGenetically Engineered MouseGrowthHomeostasisHumanImmuneImpairmentInfiltrationInflammationInflammatoryInterleukin-13KnowledgeLabelLaboratoriesLamina PropriaLinkMediatingMediator of activation proteinMicroscopyMissionMitochondriaMitochondrial DNAMitoticModelingMucous MembraneMusNatureOrganoidsOxidative StressPathogenesisPatientsPeptic EsophagitisPharmacologyProteinsPublic HealthPublicationsQuality of lifeRadiationReactive Oxygen SpeciesResearchRoleSignal TransductionSquamous EpitheliumStratified Squamous EpitheliumStructureTamoxifenTestingTight JunctionsTissuesUnited States National Institutes of HealthValidationbasecytokinedrug testingexperimental studyfood allergenhuman diseaseinflammatory milieuinnovationinsightkeratinocytemitochondrial autophagymouse modelnotch proteinnovelself-renewalstress 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
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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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
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:
$ 48.21万 - 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:
$ 48.21万 - 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:
$ 48.21万 - 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:
9367277 - 财政年份:2017
- 资助金额:
$ 48.21万 - 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:
$ 48.21万 - 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:
$ 48.21万 - 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:
$ 48.21万 - 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:
$ 48.21万 - 项目类别:
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