MicroRNAs and post-stroke angiogenesis
MicroRNA 和中风后血管生成
基本信息
- 批准号:8987275
- 负责人:
- 金额:$ 19.61万
- 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:2015-05-15 至 2015-09-14
- 项目状态:已结题
- 来源:
- 关键词:13q14AcuteAdultAffectAngiogenic FactorApoptosisAreaBindingBiologicalBlood flowBrain InfarctionCause of DeathCell Culture TechniquesCell Differentiation processCell ProliferationCellsCerebral IschemiaCerebrovascular CirculationCerebrumChromosomesChromosomes, Human, Pair 14DevelopmentDiagnosticEndothelial CellsGene ProteinsGenesGlucoseHindlimbHumanHuman GenomeIn VitroInjuryInterventionInvestigationIschemiaIschemic Brain InjuryIschemic StrokeKnockout MiceLeadLocationMediatingMessenger RNAMetabolismMicroRNAsMiddle Cerebral Artery OcclusionModelingMolecularMolecular TargetMusMyocardial InfarctionNeurologicNeurological outcomeNeuronsOutcomeOxygenPathogenesisPatientsPharmaceutical PreparationsPharmacologic SubstancePlasmaPlayProcessPrognostic MarkerProteinsProteomicsRecoveryRegulationReperfusion TherapyReportingRodentRoleSmall RNAStrokeSubfamily lentivirinaeTestingTherapeuticTherapeutic InterventionThrombolytic TherapyTimeTransgenic OrganismsUnited StatesUntranslated RegionsVascular Endothelial CellVascular Endothelial Growth FactorsVascular blood supplyangiogenesisbasecarcinogenesiscerebral arterydensitydeprivationdisabilityeffective therapygenetic approachhuman DICER1 proteinimprovednervous system disorderneurorestorationnoveloverexpressionpost strokepostnatalprotein expressionpublic health relevancerestorationspatiotemporaltherapeutic target
项目摘要
DESCRIPTION (provided by applicant): Stroke is a major cause of death and disability in the US. Unfortunately, current therapeutic options are seriously limited. Emerging evidence shows that post-ischemia angiogenesis plays a crucial role in the recovery of blood flow and neuronal metabolism after stroke. Thus, promoting angiogenesis via various approaches appears as a promising treatment for experimental ischemic stroke. MicroRNAs (miRs) function as a novel class of noncoding small RNAs that negatively modulate protein expression. MiRs have been implicated in a variety of human neurological diseases. Recent studies have revealed important roles for miRs in regulating angiogenesis. We and others have shown the involvement of miRs in the pathogenesis of ischemic brain injury, suggesting miRs as potential therapeutic targets in stroke. However, the functional significance and mechanisms of miR molecules in the regulation of angiogenic processes after stroke are poorly understood. The miR-15a/16-1 cluster is the first identified miR group associated with human carcinogenesis. Recently, dysregulated plasma miR-15a/16-1 levels are found in stroke patients, showing great potential as diagnostic and prognostic biomarkers. Inhibition of miR-15 has been shown to protect against myocardial infarction (MI). Thus, several pharmaceutical companies (MiRagen therapeutics; Servier) consider miR-15 as an important miR target to develop miR-based drugs for improving post-MI recovery. We reported for the first time that endothelial miR-15a can significantly suppress cell-autonomous angiogenesis in hindlimb ischemia. Moreover, our preliminary studies showed that the levels of the miR-15a/16-1 cluster are significantly increased in the cerebral vasculature at the penumbral area 7d after middle cerebral artery occlusion (MCAO) in mice. Of note, EC-selective miR-15a/16-1 transgenic overexpression leads to reduced cerebral microvessels and increased brain infarction in mice 7d after MCAO. Furthermore, we found that the miR-15a/16-1 cluster can bind to the 3'-UTR of vascular endothelial growth factor (VEGF) mRNA and inhibit its protein expression. These findings prompt the central hypothesis that the miR-15a/16-1 cluster functions as a critical regulator in post-ischemic cerebral angiogenesis, thus affecting long-term neurological outcomes after ischemic stroke. Three aims will be performed in this proposal. Aim 1: Determine the functional role of the miR-15a/16-1 cluster in regulating post-stroke angiogenesis; Aim 2: Identify the molecular targets of the miR- 15a/16-1 cluster in regulating post-stroke angiogenesis; Aim 3: Determine whether miR-15a/16-1-mediated angiogenesis affects long-term stroke outcomes.
描述(由适用提供):中风是美国死亡和残疾的主要原因。不幸的是,当前的治疗选择受到严重限制。新兴的证据表明,疾病后血管生成在中风后血液流量和神经元代谢的恢复中起着至关重要的作用。这是通过各种方法促进血管生成的一种实验性缺血性中风的有前途的治疗方法。 microRNA(mirs)充当一种新型的非编码小RNA,负责调节蛋白质表达。在各种人类神经系统疾病中隐含了miR。最近的研究揭示了miR在调节血管生成中的重要作用。我们和其他人表明,miR参与缺血性脑损伤的发病机理,表明miR是中风中潜在的治疗靶标。然而,对中风后血管生成过程调节中miR分子的功能意义和机制知之甚少。 miR-15a/16-1簇是与人类致癌作用相关的第一个鉴定的miR基团。最近,在中风患者中发现血浆miR-15a/16-1水平失调,作为诊断和预后生物标志物的潜力很大。抑制miR-15可预防心肌梗塞(MI)。因此,几家制药公司(Miragen)疗法;服务器)将miR-15视为开发基于miR的药物以改善MI后恢复后的重要MIR靶标。我们首次报道了内皮miR-15a可以显着抑制后肢缺血中的细胞自主血管生成。此外,我们的初步研究表明,小鼠中大脑中动脉闭塞(MCAO)后7D的大脑脉管系统中miR-15a/16-1簇的水平显着增加。值得注意的是,EC选择性miR-15A/16-1转基因过表达导致MCAO后7D小鼠的脑微血管降低,并增加了脑梗塞。此外,我们发现miR-15a/16-1簇可以与血管内皮生长因子(VEGF)mRNA的3'-UTR结合并抑制其蛋白质表达。这些发现促使中心假设是miR-15a/16-1簇是缺血后脑血管生成的关键调节剂,从而影响缺血性中风后的长期神经学结果。该提案将执行三个目标。目标1:确定miR-15a/16-1簇在控制震后血管生成中的功能作用;目标2:确定miR-15a/16-1簇的分子靶标在控制震后血管生成时; AIM 3:确定miR-15a/16-1介导的血管生成是否影响长期中风结果。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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专利数量(0)
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Jun Chen其他文献
Corrosion wear characteristics of TC4, 316 stainless steel, and Monel K500 in artificial seawater
TC4、316不锈钢、蒙乃尔K500在人工海水中的腐蚀磨损特性
- DOI:
10.1039/c7ra03065g - 发表时间:
2017-04 - 期刊:
- 影响因子:3.9
- 作者:
Jun Chen - 通讯作者:
Jun Chen
Jun Chen的其他文献
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{{ truncateString('Jun Chen', 18)}}的其他基金
BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
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10696455 - 财政年份:2023
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$ 19.61万 - 项目类别:
Adiponectin on cerebrovascular regulation in vascular cognitive impairment and dementia (VCID)
脂联素对血管性认知障碍和痴呆 (VCID) 的脑血管调节作用
- 批准号:
10542359 - 财政年份:2022
- 资助金额:
$ 19.61万 - 项目类别:
Activation of the RXR/PPARγ axis improves long-term outcomes after ischemic stroke in aged mice
RXR/PPARγ 轴的激活可改善老年小鼠缺血性中风后的长期结果
- 批准号:
10364171 - 财政年份:2022
- 资助金额:
$ 19.61万 - 项目类别:
Activation of the RXR/PPARγ axis improves long-term outcomes after ischemic stroke in aged mice
RXR/PPARγ 轴的激活可改善老年小鼠缺血性中风后的长期结果
- 批准号:
10609791 - 财政年份:2022
- 资助金额:
$ 19.61万 - 项目类别:
Methods for Analysis of Genomic Data with Auxiliary Information
具有辅助信息的基因组数据分析方法
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10188885 - 财政年份:2021
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$ 19.61万 - 项目类别:
Methods for Analysis of Genomic Data with Auxiliary Information
具有辅助信息的基因组数据分析方法
- 批准号:
10415152 - 财政年份:2021
- 资助金额:
$ 19.61万 - 项目类别:
Inflammation resolution, neuroprotection, and brain repair to promote stroke recovery
炎症消解、神经保护和大脑修复以促进中风康复
- 批准号:
9471926 - 财政年份:2017
- 资助金额:
$ 19.61万 - 项目类别:
Inflammation resolution, neuroprotection, and brain repair to promote stroke recovery
炎症消解、神经保护和大脑修复以促进中风康复
- 批准号:
10261320 - 财政年份:2017
- 资助金额:
$ 19.61万 - 项目类别:
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