Mitochondrial depolarization, mitophagy, and mitochondrial DAMPs in ALD
ALD 中的线粒体去极化、线粒体自噬和线粒体 DAMP
基本信息
- 批准号:10155373
- 负责人:
- 金额:$ 33.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-01 至 2023-04-30
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAcetaldehydeAcuteAcute Alcoholic HepatitisAgonistAlcohol dehydrogenaseAlcoholic HepatitisAlcoholic Liver DiseasesAutophagosomeBiological MarkersCYP2E1 geneCardiolipinsCessation of lifeCharacteristicsCholesterolChronicCirrhosisDevelopmentElectron MicroscopyEthanolEthanol MetabolismFK506FastingFibrosisGLP-I receptorGeneticGlucagonGoalsHepaticHepatocyteImpairmentIndividualInflammationInflammatoryInflammatory ResponseInjuryInterventionLeadLinkLiverLiver MitochondriaLiver diseasesLysosomesMediator of activation proteinMitochondriaMitochondrial DNAModalityModelingMolecularMolecular AnalysisMonitorMusNeuromuscular Depolarizing AgentsPathogenesisPatternPharmacologyPioglitazonePreventionPrevention strategyProcessRoleSerumSeveritiesSeverity of illnessTestingTherapeutic AgentsTransgenic MiceWorkalcohol exposurealdehyde dehydrogenasesbinge drinkingcytochrome cdisorder preventionexperimental studyextracellularfeedinghepatocellular injuryin vivoinnovationintravital microscopyliver developmentliver injurymortalitymultiphoton microscopynew therapeutic targetnonalcoholic steatohepatitisnovelnovel markeroxidationparkin gene/proteinpreventresponse
项目摘要
Alcoholic liver disease (ALD) accounts for ~50% of deaths due to cirrhosis and ~30% of all liver-related
deaths in the US. How ethanol damages the liver remains poorly understood, and therapies are lacking or
unproven. Our goal is to understand the pathogenesis of ALD. We observed widespread, reversible hepatic
mitochondrial depolarization (mtDepo), increased mitophagic burden and elevated serum mitochondrial DNA
(mtDNA) in mice after ethanol treatment. We propose to test the novel hypothesis that ethanol metabolism
induces mtDepo, which in turn stimulates mitophagy. Markedly increased mitophagic burden
overwhelms the capacity of lysosomes to process autophagosomes, particularly when processing of
depolarized mitochondria into mitophagosomes and then into lysosomes is compromised after
chronic ethanol exposure, leading to extracellular release of damaged mitochondria, mitophagosomes
and/or autolysosomes containing mitochondrial damage-associated molecular pattern (mtDAMP)
molecules to cause a profibrotic inflammatory response and liver injury. In Specific Aim 1 using
intravital multiphoton microscopy, we will explore if mtDepo occurs in living mice after chronic ethanol and is
exacerbated by superimposed binge drinking and in an unique fibrosis-inducing ethanol/cholesterol model we
developed. We will determine the relation of mtDepo to hepatic injury, inflammation and fibrosis. We will also
explore if inhibition of acetaldehyde (AcAld) formation by alcohol dehydrogenase and CYP2E1 deficiency,
accelerated AcAld oxidation by Alda-1, and FK506 (blocker of depolarization) decrease mtDepo and liver
injury/inflammation/fibrosis after chronic ethanol. In Aim 2, we will determine the relation of mtDepo to
mitophagy. Using genetic and pharmacological interventions in combination with intravital and electron
microscopy and analyses of molecular indicators of mitophagic flux, we will elucidate if ethanol-induced
mtDepo initiates mitophagy or if mitophagy causes mtDepo. We will determine if mitophagy/mitophagosome
processing is blunted by chronic, chronic plus cholesterol and chronic plus binge ethanol and further explore if
inhibition of autophagic processing exacerbates liver injury/inflammation/fibrosis after chronic ethanol. In Aim
3, we will characterize how mtDepo and compromised mitophagy/processing contribute to mtDAMP release
after ethanol. We will characterize release into serum of mtDAMPs after acute ethanol and chronic, chronic
plus cholesterol and chronic plus binge ethanol to determine the relationship of mtDAMP release to liver
injury/inflammation/fibrosis. We will also determine how up and down-modulation of mtDepo, mitophagy and
processing of mitophagosomes alters mtDAMP release after ethanol. This study will elucidate a novel link
between early mitochondrial changes associated with ethanol metabolism and the later development of liver
injury/inflammation/fibrosis and thus fill a critical gap in understanding ALD pathogenesis. This study should
also identify new therapeutic targets of ALD and novel biomarkers for monitoring ALD severity/progression.
酒精性肝病(ALD)占肝硬化死亡的约50%,占所有肝脏相关死亡的约30%
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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John J Lemasters其他文献
Ischemic preconditioning attenuates acute lung injury after partial liver transplantation
缺血预处理减轻部分肝移植后的急性肺损伤
- DOI:
- 发表时间:
2018 - 期刊:
- 影响因子:0
- 作者:
Qinlong Liu;Hasibur Rehman;Yasodha Krishnasamy;John J Lemasters;Zhi Zhong - 通讯作者:
Zhi Zhong
John J Lemasters的其他文献
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{{ truncateString('John J Lemasters', 18)}}的其他基金
Mechanisms of Mitochondrial Iron Uptake: New Therapeutic Targets in Hepatotoxicity
线粒体铁摄取机制:肝毒性的新治疗靶点
- 批准号:
10210670 - 财政年份:2021
- 资助金额:
$ 33.64万 - 项目类别:
Mechanisms of Mitochondrial Iron Uptake: New Therapeutic Targets in Hepatotoxicity
线粒体铁摄取机制:肝毒性的新治疗靶点
- 批准号:
10349589 - 财政年份:2021
- 资助金额:
$ 33.64万 - 项目类别:
Mechanisms of Mitochondrial Iron Uptake: New Therapeutic Targets in Hepatotoxicity
线粒体铁摄取机制:肝毒性的新治疗靶点
- 批准号:
10597049 - 财政年份:2021
- 资助金额:
$ 33.64万 - 项目类别:
Mitochondrial depolarization, mitophagy, and mitochondrial DAMPs in ALD
ALD 中的线粒体去极化、线粒体自噬和线粒体 DAMP
- 批准号:
9920650 - 财政年份:2018
- 资助金额:
$ 33.64万 - 项目类别:
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