Gene therapy for GERD-associated esophageal epithelial barrier dysfunction
GERD相关食管上皮屏障功能障碍的基因治疗
基本信息
- 批准号:10372106
- 负责人:
- 金额:$ 55.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-15 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAcidsAcute Lung InjuryAdherens JunctionAdultAnimal Disease ModelsAnimal ModelAnimalsApicalAppearanceAsthmaAutomobile DrivingBarrett EsophagusBile AcidsBlood capillariesCell Culture SystemCell Culture TechniquesCellsChronicChronic Kidney FailureClinical TrialsComplexCoughingCountryCultured CellsDevelopmentDiseaseDisease modelDistalElectroporationEpithelialEsophageal AdenocarcinomaEsophageal Squamous CellEsophagusExtracellular SpaceFamily suidaeFootball gameFunctional disorderFutureGastroesophageal reflux diseaseGastrointestinal DiseasesGene DeliveryGene TransferHeartburnHumanIn VitroIncidenceIndividualIntercellular JunctionsIonsLaryngitisLeadLungMeasurementMediatingMembraneMethodsModelingMorbid ObesityMucous MembraneMusMyocardialMyocardial InfarctionNa(+)-K(+)-Exchanging ATPaseObesityOrganoidsOryctolagus cuniculusPainPathogenesisPathologicPatientsPermeabilityPharmaceutical PreparationsPlasmidsProteinsProton Pump InhibitorsPulmonary EdemaRefluxRefractoryResistanceRiskRisk FactorsSquamous EpitheliumStomachStratificationStratified Squamous EpitheliumSymptomsSyndromeSystemTestingTight JunctionsTransfectionUp-RegulationWomanbile saltscell injuryclaudin-1 proteinearly onseteffective therapyepithelial injuryexperiencegene therapyhuman modelin vivo Modelinjuredlifetime risklung injurymenmolecular modelingnovelnovel therapeuticsoverexpressionpreventprotein complexrepairedside effectthree-dimensional modelingwater flow
项目摘要
Gastroesophageal reflux disease (GERD) is one of the most prevalent gastrointestinal disorders worldwide and
is one of the greatest risk factors in the pathogenesis of Barrett's esophagus and esophageal adenocarcinoma.
GERD is characterized by a broad spectrum of typical symptoms, such as heartburn and acid regurgitation,
and extra-esophageal manifestations, such as asthma, chronic cough and laryngitis. Although proton pump
inhibitors (PPIs) are currently the most effective treatment for GERD and its complications, up to 45% of
patients with GERD remain symptomatic on standard therapy. Long term use of PPIs can cause severe side
effects including chronic kidney disease and myocardial infarction. Thus, there is an urgent need to develop
new methods to treat PPI refractory GERD. Dilated intercellular space (DIS) in the esophageal squamous
epithelium is one of the important early pathological features in GERD. In reflux disease, gastro-duodenal
contents, the most important of which are stomach acid and bile acids, regurgitate into the distal esophagus
and cause DIS formation and loss of barrier function through epithelial injury and disruption of tight and
adherens junctions in the human esophagus as well as in animal models of the disease. Molecular analysis
has shown in patients and animal models of GERD that levels of a number of tight junction and adherens
junction proteins are reduced in this disease. Using a 3-D transwell culture of human EPC1 esophageal
squamous cells as a GERD model, we have shown that bile acid at pH 5 damaged cell junctions and causes
DIS. We have recently found that overexpression of the Na+,K+-ATPase β1 subunit by electroporation of
plasmids into healthy and injured lungs of mice and pigs protected them from subsequent lung injury and
partially reversed existing lung injury through upregulation of tight junction proteins and barrier function. We
have found similar upregulation of tight junction proteins in esophageal squamous epithelial cells following
gene transfer of the Na+,K+-ATPase β1 subunit. We hypothesize that by enhancing the levels of tight and
adherens junction complexes in the esophageal squamous epithelium by gene transfer of the Na+,K+-ATPase
β1 subunit, we may be able to prevent or reverse the appearance and consequences of DIS during
progression of GERD. Aim 1 will test whether gene transfer of the Na+,K+-ATPase β1 subunit increases,
protects, and/or restores apical junctional complexes in an in vitro stratified 3-D model of human esophageal
squamous cells and in murine esophageal organoids. Aim 2 will determine whether electroporation-mediated
gene delivery of the Na+,K+-ATPase β1 subunit to the lower esophagus in living animals can increase apical
junctional complexes. Aim 3 will determine whether electroporation-mediated gene delivery of the Na+,K+-
ATPase β1 subunit to the lower esophagus can prevent and/or treat cell junction damage and DIS in a rabbit
GERD model. These studies will provide proof of principle that this approach could be explored in future
clinical trials to prevent and treat the local effects and symptoms of GERD in patients and its consequences.
胃食管反流病(GERD)是世界范围内最常见的胃肠疾病之一
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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David A Dean其他文献
David A Dean的其他文献
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{{ truncateString('David A Dean', 18)}}的其他基金
Intracellular Trafficking of DNA for Gene Therapy
用于基因治疗的 DNA 细胞内运输
- 批准号:
10710840 - 财政年份:2023
- 资助金额:
$ 55.06万 - 项目类别:
A multimodal delivery and treatment approach for Acute Lung Injury
急性肺损伤的多模式递送和治疗方法
- 批准号:
10378509 - 财政年份:2020
- 资助金额:
$ 55.06万 - 项目类别:
Mitigating Acute Lung Injury by Cell-specific Targeting of MTOR
通过细胞特异性靶向 MTOR 减轻急性肺损伤
- 批准号:
10187645 - 财政年份:2020
- 资助金额:
$ 55.06万 - 项目类别:
Mitigating Acute Lung Injury by Cell-specific Targeting of MTOR
通过细胞特异性靶向 MTOR 减轻急性肺损伤
- 批准号:
10631224 - 财政年份:2020
- 资助金额:
$ 55.06万 - 项目类别:
Mitigating Acute Lung Injury by Cell-specific Targeting of MTOR
通过细胞特异性靶向 MTOR 减轻急性肺损伤
- 批准号:
10414888 - 财政年份:2020
- 资助金额:
$ 55.06万 - 项目类别:
A multimodal delivery and treatment approach for Acute Lung Injury
急性肺损伤的多模式递送和治疗方法
- 批准号:
10593959 - 财政年份:2020
- 资助金额:
$ 55.06万 - 项目类别:
Mitigating Acute Lung Injury by Cell-specific Targeting of MTOR
通过细胞特异性靶向 MTOR 减轻急性肺损伤
- 批准号:
10056811 - 财政年份:2020
- 资助金额:
$ 55.06万 - 项目类别:
Novel Peptide/siRNA Nanoparticles for Treatment of Acute Lung Injury
用于治疗急性肺损伤的新型肽/siRNA纳米颗粒
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9376455 - 财政年份:2017
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Development of a gene therapy approach to treat acute lung injury using a preclinical, large animal model
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8978332 - 财政年份:2014
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