Mitochondrial Dysfunction in heart Failure
心力衰竭中的线粒体功能障碍
基本信息
- 批准号:7750206
- 负责人:
- 金额:$ 28.67万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-08-14 至 2014-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdrenergic AgentsAffectAgonistBioenergeticsCanis familiarisCardiacCardiolipinsChronicCitric Acid CycleCollaborationsComplexCoronaryCultured CellsCyclic AMPCyclic AMP-Dependent Protein KinasesData AnalysesDefectDietDopamineElectron TransportElectronsEnergy MetabolismEvaluationExtravasationFailureFunctional disorderGenerationsGenesGlutamatesGoalsHeartHeart MitochondriaHeart RateHeart failureHistologyHuman ResourcesHypertrophyIndividualInner mitochondrial membraneInstructionInternationalInvestigationKnockout MiceLeft Ventricular FunctionManuscriptsMetabolicMetabolismMitochondriaMitochondrial MatrixMixed Function OxygenasesModelingModificationMusMyocardialNerveNorepinephrineOuter Mitochondrial MembraneOxidasesOxidative PhosphorylationPathway interactionsPerformancePhenotypePhosphorylationPhosphorylation SitePhosphotransferasesPortraitsPreparationPrincipal InvestigatorProductionProtein IsoformsProteinsProteomicsQuality ControlReactive Oxygen SpeciesResearch DesignRoleSamplingSerineSerine/Threonine PhosphorylationSeveritiesSignal TransductionSiteSite-Directed MutagenesisSuperoxidesTherapeuticThreonineTimeTransgenic MiceTranslationsTravelVoltage-Dependent Anion ChannelWorkadrenergiccomplex IVconstrictioncytochrome c oxidasedesignfeedinggel electrophoresisimprovedinhibitor/antagonistmRNA Expressionmeetingsmitochondrial dysfunctionmitochondrial membranenepicastatnoveloxidationpreventresearch studyrespiratory
项目摘要
The central goal of this project is to define the mechanism of myocardial bioenergetic failure in heart failure (HF)
and design therapeutic strategies targeted to improve mitochondrial energy production. We recently found a
dramatic decrease in oxidative phosphorylation (OXPHOS) of heart mitochondria in canine moderate severity
micromebolism-induced HF. The mitochondrial defect does not lie in the total amount and activity of individual
electron transport chain complexes but in their assembly in supercomplexes (respirasomes). Complex IV not
incorporated in respirasomes contains an increased content of serine and threonine phosphorylation in
mitochodria isolated from HF compared with the control. We hypothesize that HF-induced adrenergic
stimulation increases C3^osolic cAMP which is transported into the mitochondrial intermembrane space through
the mitochondrial outer membrane voltage-dependent anion channel (VDAC) and activates the mitochondrial
cAMP dependent kinase (mtPKA). mt PKA-induced phosphorylation of matrix-exposed serine and threonine
residues of cytochrome c oxidase (COX) subunits impairs the incorporation of COX into supercomplexes, reduces
the amount of fijnctional respirasomes, and decreases OXPHOS of heart mitochondria. Complexes I and III not
incorporated in respirasomes facilitate electron leakage and produce superoxide, which causes oxidative
modifications of both mitochondrial matrix and myofibrillar proteins, with decreased contractile performance.
Experiments will be performed in the well established canine coronary microembolization model ofHF,
transgenic mice and cultured cells. Specific aim 1 wil investigate mitochondrial respirasome organization,
OXPHOS, ATP production, and ROS generation in moderate severity and severe canine HF. Specific aim 2 will
identify the role of the adrenergic stimulation in disruption of the assembly of mitochondrial respirasomes in HF.
Specific aim 3 will delineate the mechanistic pathway responsible for the translation of the adrenergic signal into
mitochondrial alterations. Specific aim 4 will identify the specific mitochondrial targets for the cAMP-induced
phosphorylation and their functional consequences. Specific aim 5 proposes a rational approach for therapeutic
strategies that targets cAMP/mtPKA signaling with the attempt to prevent mitochondrial ROS generation,
RELEVANCE (See instructions):
本项目的中心目标是确定心力衰竭(HF)中心肌生物能量衰竭的机制。
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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Charles Leslie Hoppel其他文献
Charles Leslie Hoppel的其他文献
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{{ truncateString('Charles Leslie Hoppel', 18)}}的其他基金
Aged rat heart mitochondrial dysfunction: proteome and lipidome dynamics
老年大鼠心脏线粒体功能障碍:蛋白质组和脂质组动力学
- 批准号:
8969074 - 财政年份:2015
- 资助金额:
$ 28.67万 - 项目类别:
Fatty acid/branched-chain amino acid metabolism in hematopoietic stem cells
造血干细胞中的脂肪酸/支链氨基酸代谢
- 批准号:
8896218 - 财政年份:2014
- 资助金额:
$ 28.67万 - 项目类别:
Regulation of Liver CPT-I during Diabetic Ketosis
糖尿病酮症期间肝脏 CPT-I 的调节
- 批准号:
7093174 - 财政年份:2005
- 资助金额:
$ 28.67万 - 项目类别:
Regulation of Liver CPT-I during Diabetic Ketosis
糖尿病酮症期间肝脏 CPT-I 的调节
- 批准号:
6983755 - 财政年份:2005
- 资助金额:
$ 28.67万 - 项目类别:
Regulation of Liver CPT-I during Diabetic Ketosis
糖尿病酮症期间肝脏 CPT-I 的调节
- 批准号:
7417459 - 财政年份:2005
- 资助金额:
$ 28.67万 - 项目类别:
Regulation of Liver CPT-I during Diabetic Ketosis
糖尿病酮症期间肝脏 CPT-I 的调节
- 批准号:
7225597 - 财政年份:2005
- 资助金额:
$ 28.67万 - 项目类别:
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