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
基本信息
- 批准号:10414888
- 负责人:
- 金额:$ 58.94万
- 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:2020-06-15 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute Lung InjuryAcute Respiratory Distress SyndromeAddressAlveolar CellAnimal ModelAnti-Inflammatory AgentsBronchopulmonary DysplasiaCMV promoterCase StudyCell NucleusCellsCellular Metabolic ProcessCessation of lifeChronic Obstructive Pulmonary DiseaseClinicalComplementary DNACritical IllnessDNADNA Polymerase IIIDataDevelopmentDiseaseDrug TargetingEffectivenessElectroporationEndothelial CellsEndotheliumEpithelialEpithelial CellsFRAP1 geneGasesGene DeliveryGene ExpressionGene TransferGenesIn VitroIncidenceInfiltrationInflammationInflammatoryInflammatory Bowel DiseasesInjuryKnock-outKnockout MiceLeadLength of StayLungMediatingModelingMonitorMusNuclearOutcomePathogenesisPatientsPhenotypePlasmidsPreventivePublic HealthPublishingPulmonary EdemaPulmonary InflammationReportingResolutionRespiratory FailureRoleSepsisSignal TransductionSirolimusSupportive careTestingTherapeuticTumor AngiogenesisUnited StatesWorkalveolar epitheliumbasecDNA Expressioncecal ligation puncturecell growthcell injurycell typedesigneffective therapyeffectiveness evaluationexperimental studygene therapyimprovedimproved outcomeinnovationinsightknock-downlung developmentlung injurymortalitymouse modelnovelnovel strategiesnovel therapeutic interventionpreventpromoterpulmonary vascular disorderresponsesepsis induced acute lung injurysmall hairpin RNAtherapeutically effectivetransgene expressiontreatment strategyuptakevascular injury
项目摘要
Acute lung Injury (ALI) is a common cause of respiratory failure in critically ill patients. It has an incidence of ~
200,000 cases each year in the United States alone and is associated with an unacceptably high mortality rate
of 25-40% and 3.6 million hospital days in reported cases. Although, our understanding of the mechanisms
relevant to the pathogenesis and the resolution of ALI and Acute Respiratory Distress Syndrome (ARDS) has
increased during the past four decades, all current therapies for ALI/ARDS still rely on supportive care and no
effective therapeutic options are available to improve clinical outcome. Thus, the development of new treatment
strategies for ALI/ARDS that are safe, effective, and based on deeper understanding of the mechanisms involved
in ALI pathogenesis is warranted. This proposal aims to clarify the cell type-specific role of MTOR (mechanistic
[formerly mammalian] target of rapamycin) in ALI and test the utility of simultaneous but differential cell-specific
targeting of MTOR to control ALI. The proposal is based on our published and on-going work that implicates a
cell type-specific role for MTOR in inflammation; it mediates inflammation in epithelial cells whereas it serves to
limit endothelial cell inflammation. Intriguingly, however, the “net effect” of MTOR signaling results in a
proinflammatory phenotype in the lung. The proposal will address the following three inter-related, but
independent, aims. Aim 1 will test the hypothesis that MTOR limits ALI by serving an anti-inflammatory function
in pulmonary endothelium. Studies in this aim will ascertain the role of endothelial MTOR in moderating ALI by
determining the effects of modulating MTOR signaling in pulmonary endothelium on lung inflammation and injury.
Aim 2 will investigate the possibility that MTOR promotes ALI by exerting a proinflammatory function in alveolar
epithelium. Aim 2 studies will determine the role of epithelial MTOR in augmenting ALI by monitoring the effects
of modulating MTOR signaling in alveolar epithelium on lung inflammation and injury. Aim 3 will test the
hypothesis that targeting MTOR simultaneously but differentially in a cell type-specific manner (increasing it in
pulmonary endothelium but decreasing it in alveolar epithelium) will yield a superior protective and therapeutic
benefit against ALI. The proposed studies will be carried out using established mouse models of ALI and will
utilize a very new and exciting approach that uses unique cell-specific DNA nuclear targeting sequences (DTSs)
in the plasmid to direct cell-specific plasmid nuclear uptake and gene (shRNA or cDNA) expression in the desired
cell type. The plasmids will be delivered into the lungs of mice via electroporation, which yields high level of gene
expression without inducing inflammation or any cell damage to the epithelial or endothelial cell layer. The
creative use of cell-specific DTS carrying plasmid and electroporation will provide valuable insight into the cell-
specific role of MTOR in ALI and the basis for novel therapeutic approaches involving cell-specific modulation of
MTOR to control ALI.
急性肺损伤(ALI)是危重病人呼吸衰竭的常见原因。它的发生率为~
项目成果
期刊论文数量(0)
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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:
$ 58.94万 - 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:
$ 58.94万 - 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:
$ 58.94万 - 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
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10631224 - 财政年份:2020
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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
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10372106 - 财政年份:2020
- 资助金额:
$ 58.94万 - 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:
$ 58.94万 - 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:
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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
- 批准号:
9376455 - 财政年份:2017
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$ 58.94万 - 项目类别:
Development of a gene therapy approach to treat acute lung injury using a preclinical, large animal model
使用临床前大型动物模型开发治疗急性肺损伤的基因治疗方法
- 批准号:
9044084 - 财政年份:2016
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Cell-specific gene delivery methods for expression and silencing in the lung
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8978332 - 财政年份:2014
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