MicroRNAs and post-stroke angiogenesis

MicroRNA 和中风后血管生成

• 批准号: 8987275
• 负责人: Jun Chen
• 金额: $ 19.61万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/8987275
• 关键词: 13q14; Acute; Adult; Affect; Angiogenic Factor; Apoptosis; Area; Binding; Biological; Blood flow; Brain Infarction; Cause of Death; Cell Culture Techniques; Cell Differentiation process; Cell Proliferation; Cells; Cerebral Ischemia; Cerebrovascular Circulation; Cerebrum; Chromosomes; Chromosomes, Human, Pair 14; Development; Diagnostic; Endothelial Cells; Gene Proteins; Genes; Glucose; Hindlimb; Human; Human Genome; In Vitro; Injury; Intervention; Investigation; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Knockout Mice; Lead; Location; Mediating; Messenger RNA; Metabolism; MicroRNAs; Middle Cerebral Artery Occlusion; Modeling; Molecular; Molecular Target; Mus; Myocardial Infarction; Neurologic; Neurological outcome; Neurons; Outcome; Oxygen; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Plasma; Play; Process; Prognostic Marker; Proteins; Proteomics; Recovery; Regulation; Reperfusion Therapy; Reporting; Rodent; Role; Small RNA; Stroke; Subfamily lentivirinae; Testing; Therapeutic; Therapeutic Intervention; Thrombolytic Therapy; Time; Transgenic Organisms; United States; Untranslated Regions; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vascular blood supply; angiogenesis; base; carcinogenesis; cerebral artery; density; deprivation; disability; effective therapy; genetic approach; human DICER1 protein; improved; nervous system disorder; neurorestoration; novel; overexpression; post stroke; postnatal; protein expression; public health relevance; restoration; spatiotemporal; therapeutic target

 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（由申请人提供）：不幸的是，目前的治疗选择非常有限，表明缺血后血管生成在血流和神经元代谢的恢复中发挥着至关重要的作用。因此，通过各种方法促进血管生成似乎是治疗实验性缺血性中风的一种有希望的治疗方法，它是一类新型的非编码小RNA，可以负向调节蛋白质的表达。最近的研究揭示了 miR 在调节血管生成中的重要作用，表明 miR 参与了缺血性脑损伤的发病机制，这表明 miR 是中风的潜在治疗靶点。 miR 分子在中风后调节血管生成过程中的功能意义和机制知之甚少。 miR-15a/16-1 簇是最近发现的第一个与人类癌症发生失调相关的 miR 群体。在中风患者中发现血浆 miR-15a/16-1 水平，显示出作为诊断和预后生物标志物的巨大潜力，因此，多家制药公司（MiRagen Therapeutics； Servier）将 miR-15 视为开发基于 miR 的药物以改善 MI 后恢复的重要 miR 靶点，我们首次报道内皮 miR-15a 可以显着抑制。此外，我们的初步研究表明，小鼠大脑中动脉闭塞（MCAO）后7天半暗区的脑血管系统中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转基因过度表达导致小鼠7天脑微血管减少和脑梗塞增加此外，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 结合并抑制其蛋白表达，这些结果提示了 miR-15a/16-1 簇的中心假设。 15a/16-1簇在缺血后脑血管生成中发挥关键调节作用，从而影响缺血性中风后的长期神经学结果。目标1将实现三个目标：确定 miR-15a/16-1 簇在调节中风后血管生成中的功能作用；目标 2：确定 miR-15a/16-1 簇在调节中风后血管生成中的分子靶标； miR-15a/16-1 介导的血管生成影响长期中风结果。