Age-dependent use of alternative cerebral substrates during metabolic depression
代谢性抑郁症期间替代性脑基质的年龄依赖性使用
基本信息
- 批准号:8376070
- 负责人:
- 金额:$ 20.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:15 year oldAcuteAddressAdultAffectAnimalsApoptosisAreaBehavioralBiochemicalBiochemical PathwayBiochemical ProcessBiochemistryBiological AssayBrainBrain InjuriesCause of DeathCellsCerebrumChildComplementCortical ContusionsDNA DamageDNA RepairDepressed moodEffectivenessEnzymesFree RadicalsGlucoseGlucose TransporterGlycolysisHippocampus (Brain)HydroxybutyratesImmunohistochemistryInjuryKetone BodiesKetonesKetosesKetosisLaboratoriesMediatingMental DepressionMetabolicMetabolic PathwayMetabolismMotorNADHNMR SpectroscopyOutcomeOutcome MeasureOxidation-ReductionPathway interactionsPatientsPentosephosphate PathwayPentosephosphatesPhasePhysiologicalPoly(ADP-ribose) PolymerasesPotassium GlutamatePrincipal InvestigatorProcessProductionPyruvateRattusRecoveryRecovery of FunctionRelianceReportingSLC2A1 geneThalamic structureTherapeuticTimeTransport ProcessTraumatic Brain InjuryUnited StatesVenousWestern BlottingWorkage groupage relatedcognitive recoverydisabilityfeedingfunctional statusglucose metabolismglucose transporthuman tissueimprovedketogenic dietketogenticmetabolic depressionneuroprotectionoxidative DNA damageoxidative damagepediatric traumatic brain injurypostnatalrepaireduptake
项目摘要
The acute metabolic changes after traumatic brain injury (TBI) are defined by the indiscriminate release of
potassium and glutamate, transient elevation in local cerebral metabolic rate of glucose followed by
prolonged glucose metabolic depression and reduction of ATP. During this period of depressed glucose
metabolism there is an increase flux of glucose through the pentose phosphate, free radical production and
activation of poly ADP-ribose polymerase (PARP) via DMA damage. The PARP-mediated DMA repair
process requires NAD+. Depletion of the cytosolic NAD+ pool has been shown to decrease GAPDH (a key
enzyme in the glycolytic pathway) activity. Under conditions of impaired glycolytic metabolism, glucose
becomes a less favorable energy substrate. While glucose remains the primary cerebral metabolic substrate
under normal conditions, there are many physiological states during which the brain's reliance on glucose
shifts towards ketone bodies, which are the only endogenously circulating alternative substrate that can
significantly supplement cerebral metabolism. Recently, we have shown that exogenously administered R>-
hydroxybutyrate is metabolized by the adult brain and TBI-induced decrease in ATP is alleviated (Prins et al.,
2004). Our laboratory has also demonstrated the effectiveness of the ketogenic diet in reducing cortical
contusion volume by 50% following focal TBI among postnatal day 30 (PND30) and PND45 rats (Prins et al
2005). The potential to utilize ketones as an alternative substrate decreases with cerebral maturation,
suggesting that the younger brain possesses a greater ability to metabolize this substrate. The central
hypothesis of this project is that TBI-induced changes in substrate transport and glucose biochemical
processing promote age-dependent metabolism of alternative substrates during CMRglc depression. We
believe that the use of ketone bodies as an alternative cerebral metabolic substrate offers exciting
therapeutic potential following focal TBI in the developing brain and offers desperately needed treatment
options for children with TBI.
创伤性脑损伤(TBI)后急性代谢变化的定义是不加选择地释放
钾和谷氨酸,局部脑葡萄糖代谢率一过性升高,
长期的葡萄糖代谢抑制和ATP减少。在这段低血糖时期
通过磷酸戊糖的葡萄糖通量增加,自由基产生,
通过DNA损伤激活聚ADP-核糖聚合酶(PARP)。PARP介导的DNA修复
需要NAD+。细胞溶质NAD+库的耗尽已显示减少GAPDH(关键酶)。
糖酵解途径中的酶)活性。在糖酵解代谢受损的情况下,葡萄糖
变成了不太有利的能量基质。虽然葡萄糖仍然是主要的大脑代谢底物
在正常情况下,有许多生理状态,在此期间,大脑对葡萄糖的依赖
向酮体转移,酮体是唯一的内源循环替代底物,
显著补充大脑代谢。最近,我们已经表明,外源性管理R>-
羟基丁酸酯被成人脑代谢并且TBI诱导的ATP减少被减轻(Prins等人,
2004年)。我们的实验室还证明了生酮饮食在减少皮质激素方面的有效性。
在出生后第30天(PND 30)和PND 45天的大鼠中,在局灶性TBI之后,挫伤体积减少50%(Prins等人
2005年)。利用酮作为替代底物的潜力随着大脑成熟而降低,
这表明年轻的大脑具有更强的代谢这种底物的能力。中央
本项目的假设是TBI诱导的底物转运和葡萄糖生化变化
加工促进CMRglc抑制期间替代底物的年龄依赖性代谢。我们
我认为,使用酮体作为替代脑代谢底物,
在发育中的大脑中局灶性TBI后的治疗潜力,并提供迫切需要的治疗
TBI儿童的选择。
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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Mayumi Lynn Prins其他文献
Mayumi Lynn Prins的其他文献
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{{ truncateString('Mayumi Lynn Prins', 18)}}的其他基金
Cerebral Substrate Support After Traumatic Brain Injury
脑外伤后的脑基质支持
- 批准号:
10447053 - 财政年份:2018
- 资助金额:
$ 20.39万 - 项目类别:
Cerebral Substrate Support After Traumatic Brain Injury
脑外伤后的脑基质支持
- 批准号:
10199063 - 财政年份:2018
- 资助金额:
$ 20.39万 - 项目类别:
Cerebral Substrate Support After Traumatic Brain Injury
脑外伤后的脑基质支持
- 批准号:
9788536 - 财政年份:2018
- 资助金额:
$ 20.39万 - 项目类别:
Age-Dependent Ketone Metabolism After Brain Injury
脑损伤后年龄依赖性酮代谢
- 批准号:
7076205 - 财政年份:2005
- 资助金额:
$ 20.39万 - 项目类别:
Age-Dependent Ketone Metabolism After Brain Injury
脑损伤后年龄依赖性酮代谢
- 批准号:
7254100 - 财政年份:2005
- 资助金额:
$ 20.39万 - 项目类别:
Age-Dependent Ketone Metabolism After Brain Injury
脑损伤后年龄依赖性酮代谢
- 批准号:
6958787 - 财政年份:2005
- 资助金额:
$ 20.39万 - 项目类别:
Age-dependent use of alternative cerebral substrates during metabolic depression
代谢性抑郁症期间替代性脑基质的年龄依赖性使用
- 批准号:
8460076 - 财政年份:
- 资助金额:
$ 20.39万 - 项目类别:
Age-dependent use of alternative cerebral substrates during metabolic depression
代谢性抑郁症期间替代性脑基质的年龄依赖性使用
- 批准号:
8043503 - 财政年份:
- 资助金额:
$ 20.39万 - 项目类别:
Age-dependent use of alternative cerebral substrates during metabolic depression
代谢性抑郁症期间替代性脑基质的年龄依赖性使用
- 批准号:
7663688 - 财政年份:
- 资助金额:
$ 20.39万 - 项目类别:
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