Mechanisms of HIF1 alpha mediated dysregulated skeletal muscle proteostasis in alcoholic liver disease
HIF1α介导的酒精性肝病骨骼肌蛋白稳态失调的机制
基本信息
- 批准号:10579341
- 负责人:
- 金额:$ 17.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-03-01 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:AddressAdverse effectsAlcohol consumptionAlcoholic Liver CirrhosisAlcoholic Liver DiseasesAlcoholsAmmoniaAutophagocytosisAwardBiological AssayBiopsy SpecimenCareer ChoiceChromatinChronic DiseaseCirrhosisCitric Acid CycleClinicalCollaborationsComplexDataDegradation PathwayDevelopmentEnvironmentEthanolExposure toFRAP1 geneFellowshipFoundationsFundingGenetic TranscriptionGoalsHIF1A geneHeart failureHepaticHumanHyperammonemiaHypoxiaHypoxia Inducible FactorImpairmentIn VitroInstitutionKidney FailureLabelLinkLiver diseasesMediatingMentorsMetabolicMolecularMolecular TargetMorbidity - disease rateMusMuscleMuscle FibersMuscle ProteinsMuscular AtrophyNational Institute on Alcohol Abuse and AlcoholismOhioOutcomeOxygenPatientsPhenotypePhosphotransferasesPhysiciansPhysiologicalPilot ProjectsPost-Translational Protein ProcessingPre-Clinical ModelPrevalenceProtein BiosynthesisReporterReportingResearchResearch MethodologyResearch PersonnelResearch Project GrantsScientistSignal TransductionSignaling MoleculeSkeletal MuscleStressTestingTimeTissuesTrainingTranslational ResearchTransposaseUnited StatesValidationWorkalcohol consequencesalcohol exposurealcohol responsealcohol testingalcohol use disorderalpha ketoglutaratebiobankcareer developmentclinical trainingclinical translationclinically significanteffective therapyexperimental studygain of functionhepatic ureagenesisin vivoinhibitorliver transplantationloss of functionlung failuremetabolic abnormality assessmentmitochondrial dysfunctionmortalitymuscle formmuscle strengthnovelpreservationprogramsproteostasisresponsesarcopeniaskeletal muscle wastingtargeted treatmenttherapeutically effectivetissue injurytranscription factoruptake
项目摘要
The prevalence of alcohol use disorders and consequent tissue injury, primarily alcoholic liver disease (ALD)
continue to increase. Skeletal muscle loss or sarcopenia is a consistent abnormality in patients with ALD and is
associated with adverse clinical outcomes that include increased mortality, other complications of liver disease
and poor post-liver transplant outcomes. We have recently reported more severe muscle loss and a greater
rate of muscle loss in patients with alcoholic cirrhosis compared with those in other causes of cirrhosis. Despite
the high clinical significance of sarcopenia in ALD there are no effective therapeutic options because the
underlying mechanisms are not well understood. We also reported that ethanol, directly and indirectly via
impaired hepatic ammonia disposal and consequent hyperammonemia, results in a sarcopenic phenotype with
dysregulated protein homeostasis (proteostasis). In preliminary studies, we have shown mitochondrial
dysfunction in response to ethanol and hyperammonemia. We also noted that ethanol results in cataplerosis or
loss of tricarboxylic acid (TCA) cycle intermediates, specifically α-ketoglutarate (αKG) an inhibitor of HIF1α.
Consistently, unbiased approaches (assay for transposase accessible chromatin sequencing), and targeted
experiments showed oxygen independent stabilization of muscle hypoxia inducible factor-1α (HIF1α) with
ammonia. In pilot studies, we observed an increased expression of REDD1, a transcriptional target of HIF1α
and a negative regulator of the mammalian target of rapamycin complex 1 (mTORC1) that maintains skeletal
muscle proteostasis with functional responses. We also noted relative preservation of muscle mass during
hyperammonemia in muscle specific deletion of HIF1α mice. These observations formed the basis for our
hypothesis that ethanol induced hyperammonemia causes cataplerosis of αKG with oxygen independent
stabilization and impaired proteostasis and sarcopenia. We will test this hypothesis by testing if ethanol
stabilizes HIF1α in skeletal muscle, and determine the mechanisms of stabilization of muscle HIF1α. Ethanol
treatment in vitro in myotubes and in vivo in mice with loss and gain of function of HIF1α and its regulatory
molecules will be used for these studies We will also test how metabolic perturbations regulate HIF1α
stabilization and consequent molecular and functional responses in our preclinical models. Validation of key
observations will be done in human muscle tissue from our biorepository. The proposed studies will enhance
our understanding of the mechanisms of sarcopenia in ALD and lay the foundation for targeted therapeutics.
This award will provide the support and time for the applicant for a supervised research career development in
translational research. The applicant works with NIAAA funded independent investigators in the Northern Ohio
Alcohol Center and her mentor developed the field of sarcopenia in liver disease. The institutional environment
is highly supportive of her career path towards becoming an independent physician scientist focusing on
mechanistic approaches to address unmet clinical needs in patients with alcohol use disorders.
酒精使用障碍的患病率和随之而来的组织损伤,主要是酒精性肝病(ALD)
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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Nicole Welch其他文献
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{{ truncateString('Nicole Welch', 18)}}的其他基金
Mechanisms of HIF1 alpha mediated dysregulated skeletal muscle proteostasis in alcoholic liver disease
HIF1α介导的酒精性肝病骨骼肌蛋白稳态失调的机制
- 批准号:
10358594 - 财政年份:2021
- 资助金额:
$ 17.91万 - 项目类别:
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