Targeting alpha-synuclein after cerebral ischemia as a function of sex and age
Targeting alpha-synuclein after cerebral ischemia as a function of sex and age
批准号:
9891108
负责人:
Raghu VEMUGANTI
金额:
$32.91万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-04-01 至 2022-02-28
关键词:
AcuteAdultAftercareAgeAlzheimer&aposs DiseaseAmyloid beta-ProteinAnimalsApoptosisAutophagocytosisBioinformaticsBiological AssayBrainBrain InjuriesCell DeathCerebral IschemiaCerebrumChronicDataDown-RegulationEventFemaleFunctional disorderFutureGoalsHumanIndustryInfarctionInflammationIschemiaIschemic Brain InjuryKnock-outKnockout MiceLong-Term EffectsLuciferasesMediatingMicroRNAsMiddle Cerebral Artery OcclusionMitochondriaMolecularNecrosisNerve DegenerationNeurologic DysfunctionsNeuronsNuclear TranslocationOxidative StressPINK1 geneParkinson DiseasePathogenesisPathologicPathway interactionsPhasePhosphorylationPhosphotransferasesPlayProteinsRecovery of FunctionReperfusion TherapyRepressionRodentRoleRouteSerineSeveritiesSmall Interfering RNAStrokeTestingTherapeuticTimeToxic effectTransgenic MiceTranslationsTraumatic Brain InjuryTreatment EfficacyUntranslated RNAagedalpha synucleinbasecentral nervous system injuryclinical translationefficacy testingendoplasmic reticulum stressglycogen synthase kinase 3 betaknock-downmalemiddle agemonomerneurological recoveryneuron lossneuroprotectionneurotoxicnew therapeutic targetparkin gene/proteinpost strokepre-clinicalpreventpromoterprotein expressionscaffoldsexstroke therapystroke-like outcometau Proteinstau phosphorylationtherapeutic evaluationtherapeutic siRNAvectoryoung adult
中文摘要
α-突触核蛋白(α-Syn)是CNS中最丰富的蛋白质之一,已知其是中枢神经系统中的主要参与者。
帕金森氏症的神经退化我们发现,中风(短暂性局灶性缺血)
在成年啮齿类动物和人类的神经元中上调α-Syn蛋白表达和核转位。我们
进一步表明α-Syn的敲除或敲除显著降低了梗死,并促进了更好的
局部缺血的啮齿类动物的神经恢复。根据这些令人兴奋的新线索,在这
我们希望通过以下标准测试靶向α-Syn在卒中后脑中的治疗潜力
中风治疗学术产业圆桌会议(STAIR)联盟。目的1是评估
α-Syn siRNA的治疗时机窗口、性别、年龄、给药途径和毒性的影响
啮齿类动物局灶性缺血后的治疗。
我们进一步观察到一种名为miR-7a的microRNA有效地靶向α-Syn。重要的是,miR-7a显示了
与α-Syn呈负相关(miR-7a水平下调,而α-Syn水平上调)
中风)。因此,我们将测试在中风后大脑中补充miR-7a以抑制α-Syn的功效,
从而减少脑损伤。测试靶向蛋白质的替代方法提供了更好的机会,
未来的临床翻译因此,miR-7a模拟疗法将作为α-Syn siRNA的替代方法
疗法目的2:探讨性别、年龄、给药途径、
局灶性缺血后miR-7a模拟物的毒性和长期作用。
脑卒中后α-Syn介导继发性脑损伤的机制尚不清楚
明白我们证明,α-Syn蛋白在脑卒中后急性期过量形成
随着时间低聚并形成聚集体。我们进一步表明,α-Syn通过多种途径促进脑损伤,
病理机制包括线粒体分裂。在慢性神经变性中,α-Syn被认为是
GSK-3β活化和随后Tau过度磷酸化的必需支架分子
这导致Drp 1的激活,从而促进线粒体分裂。在初步研究中,我们观察到
GSK-3β、Tau和Drp 1磷酸化增加。在目标3中,我们将测试α-Syn是否促进缺血后
GSK-3β和Tau参与线粒体分裂和脑损伤。
这些研究的长期目标是评估靶向α-Syn是否是两种中风治疗的可行选择。
男性和女性以及不同的年龄。
英文摘要
Alpha-synuclein (α-Syn) is one of the most abundant proteins in the CNS that is known to be a major player in
the neurodegeneration observed in Parkinson’s disease. We show that stroke (transient focal ischemia)
upregulates α-Syn protein expression and nuclear translocation in neurons of adult rodents and humans. We
further show that knockdown or knockout of α-Syn significantly decreases the infarction and promotes better
neurological recovery in rodents subjected to focal ischemia. Based on these exciting new leads, in this
proposal we wish to test the therapeutic potential of targeting α-Syn in post-stroke brain by following the criteria
set by the Stroke Treatment Academic Industry Roundtable (STAIR) consortium. Aim 1 is to evaluate the
window of therapeutic opportunity, effect of sex, age, route of administration and toxicity of α-Syn siRNA
therapy following focal ischemia in rodents.
We further observed that a microRNA called miR-7a potently targets α-Syn. Importantly miR-7a showed an
inverse relation to α-Syn (miR-7a levels were down-regulated while α-Syn levels were upregulated after
stroke). Hence, we will test the efficacy of replenishing miR-7a in the post-stroke brain to repress α-Syn and
thus decrease brain damage. Testing alternate approaches to target a protein gives better opportunities for
future clinical translation. Hence, miR-7a mimic therapy will serve as an alternate approach to α-Syn siRNA
therapy. Aim 2 is to evaluate the window of therapeutic opportunity, effect of sex, age, route of administration,
toxicity and long-term effects of miR-7a mimic after focal ischemia.
The mechanisms that contribute to α-Syn-mediated secondary brain damage after stroke are not well
understood. We demonstrate that α-Syn protein formed in excess in brain during the acute phase after stroke
oligomerizes and forms aggregates with time. We further show that α-Syn promotes brain damage by multiple
pathologic mechanisms including mitochondrial fission. In chronic neurodegeneration, α-Syn is known to act as
an essential scaffolding molecule for the activation of GSK-3β and the subsequent Tau hyperphosphorylation
that leads to activation of Drp1 which promotes mitochondrial fission. In preliminary studies we observed
increased phosphorylation of GSK-3β, Tau and Drp1. In Aim 3, we will test if α-Syn promotes post-ischemic
mitochondrial fission and brain damage by involving GSK-3β and Tau.
The long-term goal of these studies is to evaluate if targeting α-Syn is a viable option for stroke therapy in both
males and females and at different ages.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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批准号:10664336
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项目类别:
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资助金额:$61.57万
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财政年份:2023
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负责人:Raghu VEMUGANTI
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依托单位:
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批准号:10604801
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依托单位:
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依托单位:
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依托单位:
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负责人:Raghu VEMUGANTI
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依托单位:
DNA hydroxymethylation and post stroke brain damage
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批准号:10261564
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资助金额:$41.54万
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财政年份:2018
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负责人:Raghu VEMUGANTI
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依托单位:
DNA hydroxymethylation and post stroke brain damage
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批准号:10001037
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资助金额:$41.54万
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财政年份:2018
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负责人:Raghu VEMUGANTI
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依托单位:
DNA hydroxymethylation and post stroke brain damage
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资助金额:$41.54万
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财政年份:2018
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依托单位:
Therapeutic Targeting of an lncRNA in Experimental Stroke Using STAIR Criteria
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依托单位:
Role of alpha Synuclein and microRNA 7a in post stroke brain damage
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财政年份:2015
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依托单位:
Role of alpha Synuclein and microRNA 7a in post stroke brain damage
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批准号:9281538
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资助金额:$0.0万
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财政年份:2015
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依托单位:
LncRNA FosDT mediates ischemic brain damage
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资助金额:$30.69万
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财政年份:2015
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依托单位:
Combo therapy to curtail oxidative stress after TBI
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Synergy of ER stress and oxidative stress after TBI
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资助金额:$18.81万
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财政年份:2013
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依托单位:
Synergy of ER stress and oxidative stress after TBI
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批准号:8696902
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资助金额:$22.35万
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财政年份:2013
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负责人:Raghu VEMUGANTI
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依托单位:
Combo therapy to curtail oxidative stress after TBI
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批准号:8637393
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项目类别:
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资助金额:$7.53万
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财政年份:2013
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负责人:Raghu VEMUGANTI
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依托单位:
miRNAs and PPAR-gamma-induced neuroprotection
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批准号:8338957
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资助金额:$18.81万
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负责人:Raghu VEMUGANTI
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依托单位:
海外基金