Redox Biology and Muscle Insulin Sensitivity
氧化还原生物学和肌肉胰岛素敏感性
基本信息
- 批准号:8891410
- 负责人:
- 金额:$ 35.16万
- 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
- 起止时间:2012-07-17 至 2016-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAntioxidantsBioenergeticsBiologyBuffersCell physiologyChronicCysteineDataDevelopmentDiabetes MellitusDietDietary FatsElectron TransportElectronsEngineeringEnvironmentEpidemicEquilibriumEtiologyEventFatty acid glycerol estersFire - disastersGenerationsGoalsHealthHydrogen PeroxideIn VitroInsulinInsulin ResistanceIntakeInterphase CellKineticsLeadLinkLipidsMeasuresMediatingMediator of activation proteinMembraneMetabolicMitochondriaModelingMusMuscleMuscle DevelopmentNADPH OxidaseNon-Insulin-Dependent Diabetes MellitusNutrientNutritionalObesityOxidation-ReductionPeroxisome Proliferator-Activated ReceptorsPhenotypePhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesPreventionPrevention strategyPreventiveProcessProductionProtein Serine/Threonine PhosphataseProteomePublishingPyruvate Dehydrogenase ComplexRegulationRelative (related person)Respiratory SystemRoleSeriesSignal TransductionSignaling ProteinSiteSkeletal MuscleStressSuperoxidesSystemTransgenic MiceTransgenic OrganismsWorkgenetic approachglucose uptakein vivoinsightinsulin sensitivityinsulin signalingloss of functionmouse modeloxidationpressurepreventprotective effectresearch studyrespiratoryresponsetreatment strategyvoltage
项目摘要
DESCRIPTION (provided by applicant): The underlying mechanism responsible for the development of diet-induced insulin resistance in skeletal muscle remains unresolved. Decreased insulin sensitivity is a key factor in the etiology of type 2 diabetes and, as such, identifying the underlying mechanism of insulin resistance is critical to devising appropriate prevention and treatment strategies. Recent evidence indicates high dietary fat intake increases mitochondrial hydrogen peroxide production and emission in muscle, shifting the intracellular redox environment to a more oxidized state. Blocking the hydrogen peroxide emission through the use of mitochondrial targeted antioxidants prevents the shift in cellular redox environment and preserves insulin sensitivity, providing evidence the mitochondrial respiratory system senses and initiates a counterbalance response to cellular nutritional overload. The long-term objectives of this project are to define the underlying bioenergetics mechanisms regulating mitochondrial hydrogen peroxide production/emission, to determine the impact on and integration with cellular redox systems, and to decipher the mechanism by which redox signaling networks link to the control of insulin sensitivity. The specific goals of this project ae to determine if flux through �-oxidation is a primary factor governing mitochondrial hydrogen peroxide emission, cellular redox state, and insulin sensitivity; to determine the mechanism(s) regulating hydrogen peroxide production/emission by the pyruvate dehydrogenase complex; and to determine the potential role of hydrogen peroxide induced redox regulation of phosphatase activity as a potential mediator of diet-induced insulin resistance. State-of-the-art mitochondrial function analyses as well as gain- and loss-of-function mouse models will be employed to address these goals. It is anticipated these studies will reveal new insights regarding the underlying mechanism by which metabolic imbalance leads to insulin resistance in skeletal muscle, providing the framework for devising appropriately targeted prevention and/or treatment strategies.
描述(由申请人提供):骨骼肌中饮食诱导的胰岛素抵抗发展的潜在机制仍未解决。胰岛素敏感性降低是2型糖尿病病因的关键因素,因此,确定胰岛素抵抗的潜在机制对于制定适当的预防和治疗策略至关重要。最近的证据表明,高膳食脂肪摄入会增加线粒体过氧化氢在肌肉中的产生和排放,将细胞内氧化还原环境转变为更氧化的状态。通过使用线粒体靶向抗氧化剂来阻断过氧化氢的释放,可以防止细胞氧化还原环境的转变,并保持胰岛素敏感性,这为线粒体呼吸系统感知并启动细胞营养过载的平衡反应提供了证据。该项目的长期目标是确定调节线粒体过氧化氢产生/排放的潜在生物能量学机制,确定对细胞氧化还原系统的影响和整合,并破译氧化还原信号网络与胰岛素敏感性控制联系的机制。该项目的具体目标是确定通过氧化的通量是否是控制线粒体过氧化氢排放、细胞氧化还原状态和胰岛素敏感性的主要因素;确定丙酮酸脱氢酶复合物调节过氧化氢生产/排放的机制;并确定过氧化氢诱导的磷酸酶活性的氧化还原调节作为饮食诱导的胰岛素抵抗的潜在介质的潜在作用。最先进的线粒体功能分析以及获得和失去功能的小鼠模型将被用来解决这些目标。预计这些研究将揭示代谢失衡导致骨骼肌胰岛素抵抗的潜在机制,为设计适当的针对性预防和/或治疗策略提供框架。
项目成果
期刊论文数量(11)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Rapid Repression of ADP Transport by Palmitoyl-CoA Is Attenuated by Exercise Training in Humans: A Potential Mechanism to Decrease Oxidative Stress and Improve Skeletal Muscle Insulin Signaling.
- DOI:10.2337/db14-1838
- 发表时间:2015-08
- 期刊:
- 影响因子:7.7
- 作者:Ludzki A;Paglialunga S;Smith BK;Herbst EA;Allison MK;Heigenhauser GJ;Neufer PD;Holloway GP
- 通讯作者:Holloway GP
Mitochondrial therapy improves limb perfusion and myopathy following hindlimb ischemia.
线粒体治疗可改善后肢缺血后的肢体灌注和肌病。
- DOI:10.1016/j.yjmcc.2016.05.015
- 发表时间:2016
- 期刊:
- 影响因子:5
- 作者:Ryan,TerenceE;Schmidt,CameronA;Alleman,RickJ;Tsang,AlvinM;Green,ThomasD;Neufer,PDarrell;Brown,DavidA;McClung,JosephM
- 通讯作者:McClung,JosephM
The anticancer agent doxorubicin disrupts mitochondrial energy metabolism and redox balance in skeletal muscle.
- DOI:10.1016/j.freeradbiomed.2013.08.191
- 发表时间:2013-12
- 期刊:
- 影响因子:7.4
- 作者:Gilliam, Laura A. A.;Fisher-Wellman, Kelsey H.;Lin, Chien-Te;Maples, Jill M.;Cathey, Brook L.;Neufer, P. Darrell
- 通讯作者:Neufer, P. Darrell
Looking Beyond Structure: Membrane Phospholipids of Skeletal Muscle Mitochondria.
- DOI:10.1016/j.tem.2016.05.007
- 发表时间:2016-08
- 期刊:
- 影响因子:0
- 作者:Heden TD;Neufer PD;Funai K
- 通讯作者:Funai K
Aglycemic growth enhances carbohydrate metabolism and induces sensitivity to menadione in cultured tumor-derived cells.
- DOI:10.1186/s40170-021-00241-0
- 发表时间:2021-01-19
- 期刊:
- 影响因子:5.9
- 作者:Schmidt CA;McLaughlin KL;Boykov IN;Mojalagbe R;Ranganathan A;Buddo KA;Lin CT;Fisher-Wellman KH;Neufer PD
- 通讯作者:Neufer PD
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P Darrell Neufer其他文献
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{{ truncateString('P Darrell Neufer', 18)}}的其他基金
Statins: Mitochondrial Function and Aerobic Capacity
他汀类药物:线粒体功能和有氧能力
- 批准号:
9260468 - 财政年份:2017
- 资助金额:
$ 35.16万 - 项目类别:
Statins: Mitochondrial Function and Aerobic Capacity
他汀类药物:线粒体功能和有氧能力
- 批准号:
10188421 - 财政年份:2017
- 资助金额:
$ 35.16万 - 项目类别:
Impact of organic cations on mitochondrial energetic driving forces and metabolic efficiency
有机阳离子对线粒体能量驱动力和代谢效率的影响
- 批准号:
9169876 - 财政年份:2016
- 资助金额:
$ 35.16万 - 项目类别:
Impact of organic cations on mitochondrial energetic driving forces and metabolic efficiency
有机阳离子对线粒体能量驱动力和代谢效率的影响
- 批准号:
9306069 - 财政年份:2016
- 资助金额:
$ 35.16万 - 项目类别:
Redox Biology and Muscle Insulin Sensitivity
氧化还原生物学和肌肉胰岛素敏感性
- 批准号:
8400114 - 财政年份:2012
- 资助金额:
$ 35.16万 - 项目类别:
Redox Biology and Muscle Insulin Sensitivity
氧化还原生物学和肌肉胰岛素敏感性
- 批准号:
8511626 - 财政年份:2012
- 资助金额:
$ 35.16万 - 项目类别:
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