Role of MicroRNAs in Ischemic Tolerance
MicroRNA 在缺血耐受中的作用
基本信息
- 批准号:7273884
- 负责人:
- 金额:$ 20.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-08-02 至 2008-06-30
- 项目状态:已结题
- 来源:
- 关键词:AsthmaBrainBrain IschemiaCell SurvivalCellsChromatinClassCodeContralateralDNA Microarray ChipDNA Microarray formatDataDevelopmentDiabetes MellitusDiseaseDown-RegulationEventGene ExpressionGenetic TranslationGenotypeGlucoseGoalsHepatitis CHourHuntington DiseaseIn VitroInfectionInjuryIschemiaIschemic PreconditioningLeadMacular degenerationMalignant NeoplasmsMammalian CellMessenger RNAMicroRNAsMicroarray AnalysisMiddle Cerebral Artery OcclusionModelingMolecularMolecular ProfilingMusNorthern BlottingNumbersOxygenPhenotypePolymerase Chain ReactionProteinsRNARNA InterferenceRattusRegulationResearch PersonnelRoleStroke preventionSystemTherapeutic AgentsTimeTranscriptional ActivationTranslationsUp-Regulationbasedaydeprivationin vivomind controlneuroprotectionnovelnovel therapeuticspreconditioningprogramsprotein expressionresearch studyresponse
项目摘要
DESCRIPTION (provided by applicant): Ischemic tolerance is a phenomenon whereby a sub-lethal ischemic injury, preconditioning, induces endogenous protective mechanisms that lessen the impact of a subsequent, more severe ischemic insult. We have used modeled ischemic tolerance in rat and mouse, both in vivo and in vitro, to describe multiple effectors of neuroprotection in these endogenous systems. Recently, we used DNA microarray to examine changes in gene expression in mouse brains subjected to preconditioning induced by a brief duration of ischemia, injurious ischemia, or a tolerant brain (preconditioned, then challenged with injurious ischemia). These experiments revealed that injurious ischemia up-regulated gene expression, while ischemic tolerance resulted in significant down-regulation of gene expression. Thus the signature of ischemic tolerance is that of suppressed gene expression. Elucidating the molecular mechanism(s) that underlie this focused transcriptional suppression is our goal. Eukaryotic gene expression is regulated by microRNAs, a newly identified class of small non-protein coding RNAs that regulate mRNA translation and chromatin activity in mammalian cells. Based on the signature of ischemic tolerance, a suppression of gene expression, we hypothesize that ischemic tolerance leads to regulated microRNA expression that in turn leads to the protected phenotype. In support of this hypothesis, our preliminary data show that distinct subsets of microRNAs are regulated in preconditioned, ischemic, and tolerant mouse brain. Thus to fully examine a role for microRNAs in ischemic tolerance, we propose the following specific aims: 1) establish the expression profile of microRNAs in preconditioned, ischemic, and tolerant mouse brain by microarray analysis, 2) confirm changes in, and examine the temporal expression of, microRNAs regulated in preconditioned, ischemic, and tolerant mouse brain, and 3) examine the effect of regulated microRNAs on target protein expression and cell survival. These studies are among the first to examine the regulated expression of miRNAs in response to modeled ischemia, and given the current development of short, interference RNAs as novel therapeutic agents for a number of diseases including macular degeneration, asthma, diabetes, cancer, Huntington's, and Hepatitis C infection, these studies may provide rationale for the development of similar strategies for the treatment or prevention of stroke and brain ischemia.
描述(由申请人提供):缺血耐受是一种现象,即亚致死的缺血损伤,预处理,诱导内源性保护机制,减轻随后更严重的缺血损伤的影响。我们使用了大鼠和小鼠体内和体外的缺血耐受性模型来描述这些内源性系统中神经保护的多种效应。最近,我们使用DNA微阵列来检测小鼠大脑中基因表达的变化,这些基因表达是由短暂的缺血、损伤性缺血或耐受性脑(预处理,然后再进行损伤性缺血)诱导的。这些实验表明,损伤性缺血使基因表达上调,而缺血耐受导致基因表达显著下调。因此,缺血耐受的特征是基因表达的抑制。阐明这种集中转录抑制的分子机制是我们的目标。真核生物的基因表达受microrna调控,microrna是一类新发现的非蛋白编码小rna,在哺乳动物细胞中调节mRNA翻译和染色质活性。基于缺血耐受的特征,基因表达的抑制,我们假设缺血耐受导致microRNA表达的调节,进而导致受保护的表型。为了支持这一假设,我们的初步数据显示,在预处理、缺血和耐受小鼠大脑中,不同的microrna亚群受到调节。因此,为了充分研究microrna在缺血耐受中的作用,我们提出了以下具体目标:1)通过芯片分析建立预处理、缺血和耐受小鼠大脑中microrna的表达谱;2)确认预处理、缺血和耐受小鼠大脑中microrna的变化并检测其时间表达;3)研究调控microrna对靶蛋白表达和细胞存活的影响。这些研究是第一批研究mirna在模拟缺血反应中的调控表达的研究,并且考虑到目前短干扰rna作为许多疾病(包括黄斑变性、哮喘、糖尿病、癌症、亨廷顿舞蹈症和丙型肝炎感染)的新型治疗药物的发展,这些研究可能为开发类似的治疗或预防中风和脑缺血的策略提供理论依据。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
MicroRNAs: Meta-controllers of gene expression in synaptic activity emerge as genetic and diagnostic markers of human disease.
MicroRNA:突触活性中基因表达的元控制者出现,作为人类疾病的遗传和诊断标记。
- DOI:10.1016/j.pharmthera.2011.01.004
- 发表时间:2011-04
- 期刊:
- 影响因子:13.5
- 作者:Ceman, Stephanie;Saugstad, Julie
- 通讯作者:Saugstad, Julie
Ischemic preconditioning regulates expression of microRNAs and a predicted target, MeCP2, in mouse cortex.
- DOI:10.1038/jcbfm.2009.253
- 发表时间:2010-04
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
MicroRNAs as effectors of brain function.
- DOI:10.1161/strokeaha.113.000985
- 发表时间:2013-06
- 期刊:
- 影响因子:8.3
- 作者:Saugstad JA
- 通讯作者:Saugstad JA
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JULIE Anne SAUGSTAD其他文献
JULIE Anne SAUGSTAD的其他文献
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{{ truncateString('JULIE Anne SAUGSTAD', 18)}}的其他基金
Human Cerebrospinal Fluid Extracellular Vesicles: Utility as Disease Specific Biomarkers and Impact on Alzheimer's Disease Pathology
人脑脊液细胞外囊泡:作为疾病特异性生物标志物的用途及其对阿尔茨海默病病理学的影响
- 批准号:
10661249 - 财政年份:2023
- 资助金额:
$ 20.32万 - 项目类别:
MicroRNA-Mediated Translation Initiation Arrest In Ischemic Brain
缺血性脑中 MicroRNA 介导的翻译启动停滞
- 批准号:
8637416 - 财政年份:2013
- 资助金额:
$ 20.32万 - 项目类别:
MicroRNA-Mediated Translation Initiation Arrest In Ischemic Brain
缺血性脑中 MicroRNA 介导的翻译启动停滞
- 批准号:
8729036 - 财政年份:2013
- 资助金额:
$ 20.32万 - 项目类别:
Neuroprotection by Novel Regulators of mGluR Signaling
mGluR 信号传导的新型调节剂的神经保护作用
- 批准号:
7341708 - 财政年份:2005
- 资助金额:
$ 20.32万 - 项目类别:
Neuroprotection by Novel Regulators of mGluR Signaling
mGluR 信号传导的新型调节剂的神经保护作用
- 批准号:
7033783 - 财政年份:2005
- 资助金额:
$ 20.32万 - 项目类别:
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