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)是中枢神经系统中含量最丰富的蛋白质之一,被认为是
帕金森氏症中观察到的神经变性。我们发现卒中(短暂性局灶性脑缺血)
上调成年啮齿动物和人类神经元中α-syn蛋白的表达和核转位。我们
进一步表明,α-Syn的敲除或敲除显著减少了脑梗塞,促进了更好的
局灶性脑缺血啮齿动物的神经功能恢复。基于这些令人兴奋的新线索,在这个
我们希望通过遵循以下标准来测试靶向α-Syn在卒中后脑内的治疗潜力
由中风治疗学术行业圆桌会议(STAIR)联盟设定。目标1是评估
α-Syn siRNA的治疗机会窗、性别、年龄、给药途径和毒性
啮齿类动物局灶性脑缺血后的治疗。
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显示出
与α-Syn呈负相关(MIR-7a水平下调,而α-Syn水平上调
笔划)。因此,我们将测试在卒中后脑内补充miR-7a以抑制α-syn和
从而减少对大脑的损伤。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。
心理治疗。目的2是评估治疗机会的窗口,性别,年龄,给药途径,
模拟局灶性脑缺血后miR-7a的毒性和远期效应。
α-Syn介导的卒中后继发性脑损伤的机制尚不清楚
明白了。我们证明了在卒中后的急性期,α-Syn蛋白在脑内过量形成
随着时间的推移,齐聚并形成聚集体。我们进一步表明,α-SYN通过多个途径促进脑损伤
包括线粒体分裂在内的病理机制。在慢性神经退行性变中,α-syn被认为是
一种激活GSK-3β和随后Tau过度磷酸化的必要支架分子
这会导致Drp1的激活,从而促进线粒体的分裂。在初步研究中,我们观察到
GSK-3β、Tau和DRP1的磷酸化增加。在目标3中,我们将测试α-SYN是否促进缺血后
涉及GSK-3、β和Tau的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是否是治疗两者的中风的可行选择
有男有女,年龄也不同。
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
Role of RNAs in post-stroke brain damage
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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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批准号:10618195
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依托单位:
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依托单位:
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批准号:10454793
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项目类别:
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依托单位:
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批准号:10158429
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依托单位:
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依托单位:
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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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项目类别:
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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:10462714
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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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项目类别:
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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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财政年份:2015
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依托单位:
LncRNA FosDT mediates ischemic brain damage
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批准号:9139511
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依托单位:
Combo therapy to curtail oxidative stress after TBI
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财政年份:2013
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依托单位:
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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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资助金额:$7.53万
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财政年份:2013
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依托单位:
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批准号:8338957
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资助金额:$18.81万
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依托单位:
海外基金