A novel mechanism of neurovascular protection in ischemic tolerance
缺血耐受中神经血管保护的新机制
基本信息
- 批准号:9234076
- 负责人:
- 金额:$ 33.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-05-01 至 2020-02-28
- 项目状态:已结题
- 来源:
- 关键词:AcetylcysteineAdherens JunctionAffectAlteplaseAntioxidantsAstrocytesAttenuatedBindingBlood - brain barrier anatomyBlood flowBrainCategoriesCause of DeathCellsCellular StructuresChemical StructureClinicCoculture TechniquesCysteineDataDiseaseEconomic BurdenElementsEndothelial CellsEnzymesFutureGenerationsGenesGerbilsGlutamate-Cysteine LigaseHexenalHydrogen PeroxideIn VitroInfarctionInjuryInvestigationIschemiaIschemic PreconditioningIschemic StrokeKnockout MiceLipid PeroxidationLipid PeroxidesLipidsMediatingMedicineMethodsMiddle Cerebral Artery OcclusionMusNervous System PhysiologyNeuronsNuclearOmega-3 Fatty AcidsOmega-6 Fatty AcidsOutcomeOxidative StressPathway interactionsPermeabilityPharmacologic SubstancePhasePhosphotransferasesPlayProtein BiosynthesisProteinsRattusReactionResearchResponse ElementsRoleRouteSignal TransductionSocietiesStrokeSulfhydryl CompoundsSuperoxide DismutaseSystemTXN geneTestingTranslatingWorkbasebeta-Transducin Repeat-Containing Proteinscadherin 5clinical translationdisabilityenhancing factorglycogen synthase kinase 3 betaheme oxygenase-1improvedin vivoinhibitor/antagonistmulticatalytic endopeptidase complexneuronal survivalneuroprotectionneurovascularneurovascular unitnovelparticlepreconditioningpromoterprotective effectpublic health relevancesmall hairpin RNAsocialtooltranscription factorubiquitin-protein ligase
项目摘要
DESCRIPTION (provided by applicant): Neurovascular units (NVU) are the structural and functional elements of the brain and are exquisitely susceptible to ischemic stroke. Stroke is the third leading cause of death and the leading cause of long-term disability, posing an enormous social and economic burden to society. Although the FDA has approved tissue plasminogen activator for restoring blood flow, no neuroprotective medicine is available for stroke victims. Ischemic preconditioning (IPC) has recently been shown to be able to induce ischemic tolerance of the brain against subsequent ischemic injury to the NVU; however, the underlying protective mechanisms are not clear. Using both in vitro and in vivo methods, we have obtained exciting preliminary results suggesting that IPC protects against ischemic injury via the transcription factor Nrf2 and the generation of endogenous lipid electrophiles that create mild oxidative stress. Suppressing Nrf2 or neutralizing electrophiles with N- acetylcysteine eliminates the ischemic tolerance. Electrophiles robustly activate Nrf2, induce phase 2 enzymes, and protect mouse brains, cultured rat primary cortical neurons, mouse brain microvessel endothelial cells (MBMEC), and astrocyte-endothelial cell co-cultures from ischemic injury. Furthermore, treating MBMEC cells with 4-HNE or preconditioning attenuates blood-brain barrier (BBB) damage induced by ischemia. The purpose of this proposal is to further investigate the mechanisms responsible for Nrf2 activation and neurovascular protection induced by IPC. The overall hypotheses are that IPC causes mild oxidative stress in the brain, leading to the generation of sublethal levels of lipid electrophiles; these electrophiles then activate the Nrf2 pathway by suppressing both Keap1 and GSK3ß, thereby protecting NVU components. Three specific aims are proposed: Aim 1 tests the hypotheses that IPC offers long-term neuroprotection against focal ischemia in mice and that Nrf2 and electrophiles are required for the sustained protection; Aim 2 tests the hypothesis that lipid electrophiles activate Nrf2 by inhibiting Keap1 and GSK3ß in NVU component cells; Aim 3 tests the hypothesis that IPC reinforces BBB via upreglulating CDH5 and that Nrf2 action protects the BBB and NVU in ischemic brain. This thorough investigation of the protective mechanisms of IPC may help develop future therapies that boost endogenous regulatory mechanisms in stroke victims.
描述(由申请人提供):神经血管单位(NVU)是大脑的结构和功能元件,对缺血性卒中非常敏感。中风是第三大死亡原因,也是导致长期残疾的主要原因,给社会带来巨大的社会和经济负担。虽然FDA已经批准组织纤溶酶原激活剂用于恢复血流,但没有神经保护药物可用于中风患者。缺血预处理(IPC)最近已被证明能够诱导脑缺血耐受,防止随后的NVU缺血损伤;然而,潜在的保护机制尚不清楚。使用体外和体内的方法,我们已经获得了令人兴奋的初步结果表明,IPC通过转录因子Nrf 2和产生内源性脂质亲电体,创造温和的氧化应激保护缺血性损伤。用N-乙酰半胱氨酸抑制Nrf 2或中和亲电体消除缺血耐受。亲电体稳健地激活Nrf 2,诱导2相酶,并保护小鼠脑、培养的大鼠原代皮层神经元、小鼠脑微血管内皮细胞(MBMEC)和星形胶质细胞-内皮细胞共培养物免受缺血性损伤。此外,用4-HNE或预处理处理MBMEC细胞可减轻缺血诱导的血脑屏障(BBB)损伤。本研究的目的是进一步探讨IPC诱导的Nrf 2激活和神经血管保护的机制。总体假设是IPC在大脑中引起轻度氧化应激,导致产生亚致死水平的脂质亲电体;然后这些亲电体通过抑制Keap 1和GSK 3 β激活Nrf 2通路,从而保护NVU组分。目的1验证IPC对小鼠局灶性脑缺血具有长期神经保护作用的假设,以及Nrf 2和亲电体对持续保护作用的依赖性:目的2验证脂质亲电体通过抑制NVU组分细胞中的Keap 1和GSK 3 β激活Nrf 2的假设;目的3验证IPC通过上调CDH 5增强BBB,Nrf 2作用保护缺血脑中的BBB和NVU的假设。对IPC保护机制的深入研究可能有助于开发未来的治疗方法,促进中风患者的内源性调节机制。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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