Testing a new strategy to reduce alcohol consumption by pH
测试通过 pH 值减少酒精消耗的新策略
基本信息
- 批准号:10303628
- 负责人:
- 金额:$ 18.54万
- 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:2021-09-20 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:Abdominal PainAcidsAffectAlcohol abuseAlcohol consumptionAlcohol dependenceAlcoholismAlcoholsAnion GapAstrocytesAttenuatedBicarbonatesBiological FactorsBloodBrainCell membraneCenters for Disease Control and Prevention (U.S.)Cerebrospinal FluidCessation of lifeChronicComplexConsumptionDSM-IVDevelopmentDiagnosisDietDown-RegulationFastingFeeding MethodsFoundationsFrequenciesGoalsGrantHabitsHumanHyperglycemiaIndividualIndustryInterventionIon ChannelKnockout MiceLeadMeasuresMediatingMembraneMental disordersMetabolicMetabolic acidosisMotivationMovementMusNational Institute on Alcohol Abuse and AlcoholismNausea and VomitingNervous system structureNeurogliaNeuronsNeurotransmitter ReceptorNucleus AccumbensPatternPharmaceutical PreparationsPrevention strategyProceduresPropertyProteinsRegulationRelapseReportingResearchResearch PersonnelRewardsRiskRoleSedation procedureSeveritiesStructureSurveysSynapsesSynaptic CleftSynaptic TransmissionTestingVentral Tegmental AreaWorld Health Organizationaddictionalcohol abuse therapyalcohol rewardalcohol use disorderbasebinge drinkerclinically relevantdrinkingfeedingmesolimbic systemmouse modelnovel strategiesoverexpressionproblem drinkerpsychologicrestorationrisk minimizationsobriety
项目摘要
Summary
pH is an important biological factor in the nervous system, where it alters the structure and activity of numerous
proteins including neurotransmitter receptors, ion channels, and synaptic transmission machinery. It may affect
neuronal activities in the circuits responsible for alcohol reward value or alcohol modulatory properties, thereby
changing alcohol consumption. This project explores the possibility of reducing alcohol consumption by
changing brain pH. We recently reported that knockout mice lacking the pH-regulating transporter NBCn1 fail
to maintain normal pH in neurons, causing decreased intracellular pH and decreased cerebrospinal fluid pH.
Interestingly, these mice drink more alcohol and develop an increase in the reward value of alcohol.
Furthermore, NBCn1 is downregulated in mice chronically fed with alcohol and humans with alcohol use
disorder (AUD). Thus, abnormal function in NBCn1 not only influences alcohol consumption, but is also
induced by alcohol consumption. The central hypothesis based on our previous and preliminary studies is that
alcohol causes NBCn1 downregulation and this downregulation reduces brain pH and subsequently increases
alcohol consumption. The goal of the project is to obtain more information on the role of NBCn1-mediated pH
regulation in alcohol consumption and to provide a foundation for development of pH-dependent strategies to
reduce consumption. Achieving this goal will be important for understanding propensity toward alcoholic
ketoacidosis (AKA) and developing a prevention strategy. AKA is a metabolic acidosis induced after binge or
chronic alcohol abuse followed by fasting. It is characterized by hyperketonemia and high anion gap metabolic
acidosis without significant hyperglycemia, and causes nausea, vomiting, and abdominal pain. Two specific
aims are set to achieve the goal. Aim 1 will examine the effects of pH restoration on increased alcohol
consumption in NBCn1 knockout mice. The efficacy of pH in reducing alcohol consumption and NBCn1
involvement in this pH effect will be investigated. A mechanistic approach will then be used by injecting NBCn1
to the mouse brain, primarily in the mesolimbic system. Aim 2 will examine the effects of pH on AKA in mice.
We developed a mouse model of AKA using a clinically relevant alcohol feeding procedure. We will test
whether adjusting systemic pH attenuates AKA and whether NBCn1 is involved. Bicarbonate will be added to
the diet and AKA induction and severity will be measured. We will also examine NBCn1 expression and activity
during AKA development. In addition, the effects of NBCn1 overexpression in the mesolimbic system will be
assessed. The results will provide unprecedented information about the pH effects on alcohol consumption and
NBCn1 involvement in producing these effects. We anticipate that the project will lead to the establishment of a
new research platform for pH-dependent strategies to reduce alcohol consumption for ordinary drinkers who
want to drink less, and chronic or binge drinkers who could be metabolically complicated with AKA.
总结
项目成果
期刊论文数量(0)
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{{ truncateString('INYEONG CHOI', 18)}}的其他基金
Testing a new strategy to reduce alcohol consumption by pH
测试通过 pH 值减少酒精消耗的新策略
- 批准号:
10491351 - 财政年份:2021
- 资助金额:
$ 18.54万 - 项目类别:
Structure/function analysis of the na/bicarbonate cotransporters
na/碳酸氢盐协同转运蛋白的结构/功能分析
- 批准号:
7931611 - 财政年份:2009
- 资助金额:
$ 18.54万 - 项目类别:
Structure/function analysis of the na/bicarbonate cotransporters
na/碳酸氢盐协同转运蛋白的结构/功能分析
- 批准号:
7448573 - 财政年份:2007
- 资助金额:
$ 18.54万 - 项目类别:
Structure/function analysis of the na/bicarbonate cotransporters
na/碳酸氢盐协同转运蛋白的结构/功能分析
- 批准号:
8126250 - 财政年份:2007
- 资助金额:
$ 18.54万 - 项目类别:
Structure/function analysis of the na/bicarbonate cotransporters
na/碳酸氢盐协同转运蛋白的结构/功能分析
- 批准号:
7648019 - 财政年份:2007
- 资助金额:
$ 18.54万 - 项目类别:
Structure/function analysis of the na/bicarbonate cotransporters
na/碳酸氢盐协同转运蛋白的结构/功能分析
- 批准号:
7321959 - 财政年份:2007
- 资助金额:
$ 18.54万 - 项目类别:
Structure/function analysis of the na/bicarbonate cotransporters
na/碳酸氢盐协同转运蛋白的结构/功能分析
- 批准号:
7893584 - 财政年份:2007
- 资助金额:
$ 18.54万 - 项目类别:
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