Mitochondrial DNA repair agents for acute lung injury
Mitochondrial DNA repair agents for acute lung injury
批准号:
8313376
负责人:
MARK N GILLESPIE
金额:
$15.48万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2012
资助国家:
美国
项目状态:
已结题
起止时间:
2012-07-15 至 2014-07-14
关键词:
AcuteAcute Lung InjuryAdult Respiratory Distress SyndromeAntioxidantsBlood VesselsBusinessesCell DeathCell Fate ControlCell SurvivalCellsChimeric ProteinsClinicalClinical ResearchClinical TrialsCultured CellsDNA RepairDNA Repair EnzymesDNA glycosylaseDNA repair proteinDirect CostsDiseaseDrug effect disorderEffectivenessEtiologyFetal LungFunctional disorderGeneticHydrogen PeroxideHyperoxiaInjuryInterventionIschemiaLaboratory StudyLegal patentLungLung TransplantationMediatingMitochondriaMitochondrial DNAModelingMolecularMolecular TargetNatureNew AgentsOutcomeOxidantsPatientsPharmaceutical PreparationsPhasePlanet MarsPlayPopulationPseudomonas aeruginosaRattusReactive Oxygen SpeciesRecording of previous eventsRecoveryRelative (related person)Reperfusion InjuryReperfusion TherapyResearch PersonnelRiskRodent ModelRoleRouteSentinelSignal TransductionTestingTherapeuticTimeTransplantationUncertaintyUniversitiesVascular Endothelial CellVentilatorWorkbasecell typeclinically relevantcommercializationcost effectivecytotoxicitydesigndrug developmentexpectationimprovedinnovationlung injurylung ischemiamortalitynoveloxidant stresspreventrepairedresearch studyresponse
中文摘要
描述(由申请人提供):急性肺损伤(ALI)的药物开发因未实现的期望而受到损害。也许最能说明这种令人不满意的情况的是
英文摘要
DESCRIPTION (provided by applicant): Drug development for acute lung injury (ALI) has been marred by unfulfilled expectations. Perhaps best illustrating this unsatisfactory situation is
the history of therapeutic strategies directed at inhibition of reactive oxygen species (ROS). While decades of laboratory and clinical studies make it clear that ROS are pathogenically important across the entire spectrum of ALI/ARDS, beneficial effects of anti-oxidants in clinical trials have been unimpressive. These negative outcomes may be attributed in part to the heterogeneous nature and onset of ALI/ARDS which tends to obfuscate design and interpretation of clinical trials, and partly to the scientific uncertainty about molecular targetsof anti-oxidant drug action. Currently available strategies may not target the key sentinel molecule(s) integrating cellular effects of ROS. Multiple lines of evidence support the idea that mtDNA serves as a molecular sentinel controlling cell fate in response to oxidant stress. Indeed, genetic modulation of the first and rate-limiting step in mtDNA repair - mediated by Ogg1, a DNA glycosylase excises oxidatively damaged bases - coordinately regulates ROS-induced mtDNA damage and cell death in all cultured cell populations so far studied. Based on these provocative findings, the small business concern, Exscien, and its university investigators devised and patented novel fusion protein constructs targeting DNA repair glycosylases to mitochondria and demonstrated in clinically-relevant rodent models that the new agents exert no off-target effects, prevent oxidative mtDNA damage, and suppress lung injury and mortality. We now propose to verify the efficacy of mt-targeted DNA repair "drugs" in ALI of a specific etiology - Ischemia-Reperfusion (IR) injury in the setting of lung transplant. The significance of this Phase I proposal lies in its focus on transplant-related lung IR injury which should reduce the time and expense required for commercialization. This application is innovative because the proposed experiment will herald first-in-class, platform molecules directed against a novel pharmacologic target in ALI - mtDNA - and many other disorders wherein oxidant stress plays a pathogenic role.
PUBLIC HEALTH RELEVANCE: There are currently no pharmacotherapeutic interventions to treat ALI. In a related context, while reactive oxygen species play a role in these disorders, non-selective anti-oxidants have proven ineffective. Herein we will test a new concept - that repair of
oxidative mtDNA damage directs cell fate decisions in ALI - which, if valid, will point to an entirely new pharmacologic strategy for treating ALI and related disorders.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
mtDNA damage and DAMPs in multiple organ dysfunction syndrome
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批准号:10092191
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项目类别:
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资助金额:$43.86万
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财政年份:2019
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负责人:MARK N GILLESPIE
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依托单位:
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批准号:9921454
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项目类别:
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资助金额:$43.86万
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财政年份:2019
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负责人:MARK N GILLESPIE
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依托单位:
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批准号:10353371
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资助金额:$43.86万
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财政年份:2019
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依托单位:
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批准号:8276921
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资助金额:$37.13万
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批准号:9111928
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资助金额:$153.84万
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财政年份:2012
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依托单位:
MtDNA repair: An isolated pharmacologic target in acute lung injury
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批准号:9020265
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项目类别:
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资助金额:$37.13万
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财政年份:2012
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负责人:MARK N GILLESPIE
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依托单位:
MtDNA repair: An isolated pharmacologic target in acute lung injury
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批准号:8460071
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项目类别:
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资助金额:$35.34万
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财政年份:2012
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负责人:MARK N GILLESPIE
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依托单位:
MtDNA repair: An isolated pharmacologic target in acute lung injury
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批准号:8824557
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项目类别:
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资助金额:$36.57万
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财政年份:2012
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负责人:MARK N GILLESPIE
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依托单位:
MtDNA repair: An isolated pharmacologic target in acute lung injury
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批准号:10206228
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项目类别:
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资助金额:$41.84万
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财政年份:2012
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负责人:MARK N GILLESPIE
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依托单位:
MtDNA repair: An isolated pharmacologic target in acute lung injury
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批准号:8610348
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项目类别:
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资助金额:$36.38万
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财政年份:2012
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负责人:MARK N GILLESPIE
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依托单位:
DNA modifications in primary pulmonary hypertension
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批准号:7268063
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项目类别:
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资助金额:$17.81万
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财政年份:2006
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负责人:MARK N GILLESPIE
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依托单位:
Mitochondrial DNA Integrity and Endothelial Free Radical Stress
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批准号:7217672
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项目类别:
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资助金额:$29.99万
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财政年份:2006
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负责人:MARK N GILLESPIE
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依托单位:
DNA modifications in primary pulmonary hypertension
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批准号:7071572
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项目类别:
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资助金额:$19.83万
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财政年份:2006
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负责人:MARK N GILLESPIE
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依托单位:
Lung Cell Genomic Threats from Physiological Signals
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批准号:7034624
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项目类别:
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资助金额:$35.64万
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财政年份:2005
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负责人:MARK N GILLESPIE
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依托单位:
Lung Cell Genomic Threats from Physiological Signals
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批准号:7201652
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项目类别:
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资助金额:$34.61万
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财政年份:2005
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负责人:MARK N GILLESPIE
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依托单位:
Lung Cell Genomic Threats from Physiological Signals
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批准号:7571582
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项目类别:
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资助金额:$34.61万
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财政年份:2005
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负责人:MARK N GILLESPIE
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依托单位:
Lung Cell Genomic Threats from Physiological Signals
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批准号:7385098
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项目类别:
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资助金额:$34.61万
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财政年份:2005
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负责人:MARK N GILLESPIE
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依托单位:
Lung Cell Genomic Threats from Physiological Signals
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批准号:6926826
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项目类别:
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资助金额:$36.5万
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财政年份:2005
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负责人:MARK N GILLESPIE
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依托单位:
Mitochondrial DNA Integrity and Endothelial Cell Free Radical Stress
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批准号:6631291
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项目类别:
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资助金额:$25.75万
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财政年份:2002
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负责人:MARK N GILLESPIE
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依托单位:
Mitochondrial DNA Integrity and Endothelial Free Radical Stress
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批准号:7897854
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项目类别:
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资助金额:$35.66万
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财政年份:2001
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负责人:MARK N GILLESPIE
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依托单位:
海外基金