Involvement of Permeability Transition Pore in Developmental Alcohol Neurotoxicit
渗透性转变孔参与发育性酒精神经毒性
基本信息
- 批准号:7386219
- 负责人:
- 金额:$ 21.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-04-15 至 2010-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdenine NucleotidesAffectAffinityAgeAlcohol abuseAlcohol-Related Neurodevelopmental DisorderAlcoholsAnimal ModelAnimalsApoptosisApoptoticBax proteinBehavioralBindingBinding SitesBiochemicalBioenergeticsBiological ModelsBirthBongkrekic AcidBrainCell DeathCell Membrane PermeabilityCellsCerebellumCessation of lifeCharacteristicsComplexConditionCongenital AbnormalityConsumptionCoupledDataDetergentsDevelopmentDissociationDoseElementsEnzyme-Linked Immunosorbent AssayEnzymesEthanolEventExposure toFetal Alcohol ExposureFetal Alcohol SyndromeGlucoseGrowthHepatocyteHoloenzymesHomoHumanInvestigationIsoelectric FocusingLaboratoriesLate EffectsLong-Evans RatsMediatingMembraneMethodsMitochondriaModelingNeonatalNervous system structureNeuraxisNeuronsOxidative PhosphorylationPermeabilityPhysiologicalPore ProteinsPredispositionPrevalenceProbabilityProtein DephosphorylationProteinsRattusRecombinantsResearchResistanceRodentRoleSamplingSilicon DioxideSimulateSiteStagingStandards of Weights and MeasuresStimulusTechniquesTestingTherapeuticTherapeutic AgentsTherapeutic InterventionThird Pregnancy TrimesterToxic effectUnited StatesVoltage-Dependent Anion Channelalcohol effectalcohol exposurealcohol sensitivitybasebinge drinkingcaspase-3cell typedaydesigngenetic regulatory proteinglucose metabolismgranule cellhexokinasein vivokillingsmembermitochondrial membranemitochondrial permeability transition poreneonateneurobehavioralneuron lossneurotoxicneurotoxicitynovelpostnatalprenatal exposureprotein protein interactionpup
项目摘要
DESCRIPTION (provided by applicant): Animal fetal alcohol syndrome (FAS) models have demonstrated a temporal window during the brain growth spurt in which cerebellum is particularly vulnerable to the neurotoxic effects of ethanol (EtOH). In rodents, the brain growth spurt period occurs during postnatal day 4 (P4) through P10. In humans, this developmental stage occurs during the third trimester of pregnancy when neurobehavioral abnormalities associated with FAS are introduced. Rat cerebellum is particularly sensitive to EtOH during P4-6. At a slightly later neonatal period (P7 and later), the effects of comparable exposure are minimal. During the brain growth spurt, many neurons undergo apoptosis. This EtOH-mediated neuronal death is primarily Bax-dependent. There are two known general mechanisms by which Bax induces mitochondria to release apoptotic death effectors: 1) Bax can directly interact with the mitochondrial permeability transition pore (PTP) to prolong its opening [PTP-dependent]; or, 2) Bax molecules can homo-oligomerize to create a channel in the mitochondrial membrane [PTP-independent]. Under most apoptotic conditions, apoptotic activation is PTP-independent. Under physiological conditions (e.g., no interaction with Bax), regulatory proteins connect oxidative phosphorylation to glucose metabolism and maintain membrane integrity. The mechanism by which EtOH mediates mitochondrial-activated apoptosis at this pivotal point is unknown. However, based on previous studies and preliminary data, we hypothesize that during a period of maximum EtOH susceptibility (P4), EtOH-mediated apoptosis in the rat cerebellum is activated by the PTP-dependent Bax mechanism. At a slightly later more EtOH resistant period (P7), we hypothesize that EtOH effects on PTP regulatory proteins are minimal. This proposed investigation uniquely addresses the role of PTP regulatory proteins specific to alcohol neurotoxicity in developing neurons. Additionally, it tests a novel, potential regulatory mechanism of Bad-a Bax-supporting protein-which we speculate promotes apoptosis in cerebellum of P4 EtOH-exposed animals by binding and sequestering mitochondrial hexokinase, a glucose metabolizing enzyme. For the proposed research, Long-Evans rats are exposed to a single dose of EtOH on P4 and P7. Novel elements used for this in vivo investigation include: 1) isoelectric focusing to identify the mechanism of Bax-dependent apoptotic activation induced by EtOH; and, 2) an ELISA-based technique recently developed in our laboratory (Siler-Marsiglio et al., 2005a, 2006) that detects and quantifies potential competing native protein-protein interactions. Analyses of differential regulatory protein-protein interactions in cerebellum at EtOH-sensitive compared to EtOH-resistant ages are important for revealing mechanisms critical to developmental EtOH neurotoxicity, and will be particularly important in identifying possible sites for eventual therapeutic intervention.
描述(由申请人提供):动物胎儿酒精综合征(FAS)模型已证明在脑生长突增期间存在一个时间窗,其中小脑特别容易受到乙醇(EtOH)的神经毒性作用的影响。在啮齿类动物中,大脑生长突增期发生在出生后第4天(P4)至P10。在人类中,这一发育阶段发生在妊娠晚期,此时引入了与FAS相关的神经行为异常。大鼠小脑在P4-6期间对EtOH特别敏感。在稍晚的新生儿期(P7及以后),类似暴露的影响很小。在大脑生长突增期间,许多神经元发生凋亡。这种EtOH介导的神经元死亡主要是依赖性的。有两种已知的Bax诱导线粒体释放凋亡死亡效应物的一般机制:1)Bax可以直接与线粒体通透性转换孔(PTP)相互作用以延长其开放[PTP依赖性];或2)Bax分子可以同源寡聚化以在线粒体膜中创建通道[PTP非依赖性]。在大多数凋亡条件下,凋亡激活是PTP非依赖性的。在生理条件下(例如,不与Bax相互作用),调节蛋白将氧化磷酸化与葡萄糖代谢联系起来并维持膜完整性。EtOH在这个关键点介导神经细胞活化凋亡的机制尚不清楚。然而,根据以前的研究和初步数据,我们假设,在一段时间的最大乙醇敏感性(P4),乙醇介导的大鼠小脑细胞凋亡激活的PTP依赖的Bax机制。在稍晚的EtOH抵抗期(P7),我们假设EtOH对PTP调节蛋白的影响是最小的。这项拟议的调查独特地解决了PTP调节蛋白的作用,具体到酒精神经毒性在发育中的神经元。此外,它还测试了Bad-a Bax支持蛋白的一种新型潜在调节机制,我们推测该机制通过结合和隔离线粒体己糖激酶(一种葡萄糖代谢酶)来促进P4 EtOH暴露动物小脑的细胞凋亡。对于所提出的研究,Long-Evans大鼠在P4和P7暴露于单剂量的EtOH。用于该体内研究的新元件包括:1)等电聚焦,以鉴定由EtOH诱导的细胞凋亡依赖性活化的机制;和2)我们实验室最近开发的基于ELISA的技术(Siler-Marsiglio et al.,2005 a,2006),其检测和定量潜在的竞争性天然蛋白质-蛋白质相互作用。在EtOH敏感的小脑相比,EtOH耐药年龄的差异调节蛋白质-蛋白质相互作用的分析是重要的,揭示机制的关键发育EtOH神经毒性,并将在确定可能的网站,最终的治疗干预特别重要。
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)
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MARIETA B HEATON其他文献
MARIETA B HEATON的其他文献
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{{ truncateString('MARIETA B HEATON', 18)}}的其他基金
Critical Mechanisms Underlying THC Neurotoxicity in Developing CNS
THC 对中枢神经系统发育的神经毒性的关键机制
- 批准号:
9222525 - 财政年份:2017
- 资助金额:
$ 21.06万 - 项目类别:
Involvement of Permeability Transition Pore in Developmental Alcohol Neurotoxicit
渗透性转变孔参与发育性酒精神经毒性
- 批准号:
7614292 - 财政年份:2008
- 资助金额:
$ 21.06万 - 项目类别:
Ethanol and Bcl-2 Gene Interactions in the Developing CNS
中枢神经系统发育中的乙醇和 Bcl-2 基因相互作用
- 批准号:
8248337 - 财政年份:2001
- 资助金额:
$ 21.06万 - 项目类别:
ETHANOL AND BCL-2 GENE INTERACTIONS IN DEVELOPING CNS
乙醇和 BCL-2 基因在中枢神经系统发育中的相互作用
- 批准号:
6629635 - 财政年份:2001
- 资助金额:
$ 21.06万 - 项目类别:
ETHANOL AND BCL-2 GENE INTERACTIONS IN DEVELOPING CNS
乙醇和 BCL-2 基因在中枢神经系统发育中的相互作用
- 批准号:
6890029 - 财政年份:2001
- 资助金额:
$ 21.06万 - 项目类别:
ETHANOL AND BCL-2 GENE INTERACTIONS IN DEVELOPING CNS
乙醇和 BCL-2 基因在中枢神经系统发育中的相互作用
- 批准号:
6509313 - 财政年份:2001
- 资助金额:
$ 21.06万 - 项目类别:
ETHANOL AND BCL-2 GENE INTERACTIONS IN DEVELOPING CNS
乙醇和 BCL-2 基因在中枢神经系统发育中的相互作用
- 批准号:
6735668 - 财政年份:2001
- 资助金额:
$ 21.06万 - 项目类别:
Ethanol and Bcl-2 Gene Interactions in the Developing CNS
中枢神经系统发育中的乙醇和 Bcl-2 基因相互作用
- 批准号:
7660477 - 财政年份:2001
- 资助金额:
$ 21.06万 - 项目类别:
Ethanol and Bcl-2 Gene Interactions in the Developing CNS
中枢神经系统发育中的乙醇和 Bcl-2 基因相互作用
- 批准号:
7795256 - 财政年份:2001
- 资助金额:
$ 21.06万 - 项目类别:
Ethanol and Bcl-2 Gene Interactions in the Developing CNS
中枢神经系统发育中的乙醇和 Bcl-2 基因相互作用
- 批准号:
7370981 - 财政年份:2001
- 资助金额:
$ 21.06万 - 项目类别:
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