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)是中枢神经系统中最丰富的蛋白质之一,在神经系统中起着重要的作用
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:
Epitranscriptomic regulation by m6A RNA methylation after stroke
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批准号:10604801
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项目类别:
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资助金额:$61.81万
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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:
BLRD Research Career Scientist Award Application
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批准号:10618195
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项目类别:
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资助金额:$0.0万
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财政年份:2021
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负责人:Raghu VEMUGANTI
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依托单位:
miR-21 induced neuroprotection after stroke
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批准号:10513282
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项目类别:
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资助金额:$0.0万
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财政年份:2021
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负责人:Raghu VEMUGANTI
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依托单位:
BLRD Research Career Scientist Award Application
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批准号:10373075
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项目类别:
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资助金额:$0.0万
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财政年份:2021
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负责人:Raghu VEMUGANTI
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依托单位:
Neuroprotection after TBI
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批准号:10454793
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项目类别:
-
资助金额:$0.0万
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财政年份:2019
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负责人:Raghu VEMUGANTI
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依托单位:
Neuroprotection after TBI
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批准号:10158429
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项目类别:
-
资助金额:$0.0万
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财政年份:2019
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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:9757829
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项目类别:
-
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:10261564
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项目类别:
-
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:
-
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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项目类别:
-
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:
Therapeutic Targeting of an lncRNA in Experimental Stroke Using STAIR Criteria
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批准号:9323794
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项目类别:
-
资助金额:$42.17万
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财政年份:2017
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负责人:Raghu VEMUGANTI
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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:8924344
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项目类别:
-
资助金额:$0.0万
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财政年份:2015
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负责人:Raghu VEMUGANTI
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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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项目类别:
-
资助金额:$0.0万
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财政年份:2015
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负责人:Raghu VEMUGANTI
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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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项目类别:
-
资助金额:$30.69万
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财政年份:2015
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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:8735202
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项目类别:
-
资助金额:$7.45万
-
财政年份:2013
-
负责人:Raghu VEMUGANTI
-
依托单位:
Synergy of ER stress and oxidative stress after TBI
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批准号:8598653
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项目类别:
-
资助金额:$18.81万
-
财政年份:2013
-
负责人:Raghu VEMUGANTI
-
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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项目类别:
-
资助金额:$22.35万
-
财政年份:2013
-
负责人:Raghu VEMUGANTI
-
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:
-
资助金额:$7.53万
-
财政年份:2013
-
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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项目类别:
-
资助金额:$18.81万
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财政年份:2012
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负责人:Raghu VEMUGANTI
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依托单位:
海外基金