Long Non-Coding RNAs and Cerebral Angiogenesis in Ischemic Stroke

长非编码 RNA 与缺血性中风中的脑血管生成

• 批准号: 10605296
• 负责人: Dandan Sun
• 金额: $ 36.78万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605296
• 关键词: Acute; Adult; Affect; Alternative Splicing; Angiogenesis Inhibitors; Angiogenic Factor; Area; Biological Process; Blood flow; Cause of Death; Cell Proliferation; Cells; Cerebral Ischemia; Cerebrovascular system; Cerebrum; Development; Dosage Compensation (Genetics); Endothelial Cells; Endothelium; Epigenetic Process; Functional disorder; Gene Expression; Gene Modified; Genes; Genetic; Genomic Imprinting; Growth; Hindlimb; Human; Intervention; Investigation; Ischemia; Ischemic Brain Injury; Ischemic Stroke; MALAT1 gene; Malignant Neoplasms; Mediating; Middle Cerebral Artery Occlusion; Molecular; Molecular Target; Mus; Neurological outcome; Non-Small-Cell Lung Carcinoma; Nuclear; Organogenesis; Pathogenesis; Pathologic; Physiological Processes; Play; Post-Transcriptional RNA Processing; Proteins; Recovery; Recovery of Function; Regulation; Rodent; Role; Small RNA; Stroke; Technology; Testing; Therapeutic; Therapeutic Intervention; Thrombolytic Therapy; Time; Transgenic Mice; Transgenic Organisms; United States; Untranslated RNA; Vascular blood supply; Vegf inhibition; age effect; angiogenesis; cell motility; cerebral artery; cerebral atrophy; cerebral microvasculature; chromatin remodeling; density; disability; effective therapy; human disease; improved; ischemic injury; long term recovery; mRNA Expression; myogenesis; nervous system disorder; neuronal metabolism; neurorestoration; novel; overexpression; post stroke; post-stroke angiogenesis; posttranscriptional; protein expression; restoration; stroke model; stroke outcome; synaptogenesis; therapeutic target; transcriptome sequencing

Extensive evidence has shown that post-ischemia angiogenesis contributes to the improvement of blood flow and neurological outcomes in stroke. Cerebral ischemia rapidly triggers the induction of a variety of genes and proteins that are involved in angiogenesis. Interventions that enhance these pro-angiogenic factors are a promising therapeutic strategy for long-term functional recovery after ischemic stroke. Long non-coding RNAs (lncRNAs) function as a novel class of noncoding RNAs that modulate gene or protein expression. In addition to their critical role in various biological processes, lncRNAs have also been implicated in a variety of human neurological diseases. We and others have recently uncovered the essential role of lncRNAs in the pathogenesis of ischemic injury in rodent stroke models, suggesting that lncRNAs are potential therapeutic targets. However, the functional significance and molecular mechanisms of lncRNAs in angiogenesis and late stage of neurological outcomes after ischemic stroke are poorly understood. Metastasis associated lung adenocarcinoma transcript 1 (Malat1) is one of the first identified lncRNAs associated with human cancers. Cumulative studies have shown that Malat1 plays pivotal roles in multiple pathological conditions as well. Previously, we were the first to identify that (Malat1) is one of the most highly upregulated stroke-responsive endothelial lncRNAs by using RNA-sequencing technology, and its dysfunction contributes to acute ischemic brain injury. We also demonstrated that Malat1 can significantly suppress cell- autonomous angiogenesis in hindlimb ischemia. Moreover, our preliminary studies showed that Malat1 levels are significantly increased in the cerebral vasculature of the penumbral area 7d after middle cerebral artery occlusion (MCAO) in mice. Of note, genetic deletion of Malat1 leads to reduced cerebral microvessel density and increased brain atrophy in mice 28d after MCAO, whereas EC-selective transgenic overexpression of the Malat1 gene increases post-ischemic cerebral angiogenesis in mice. Furthermore, we found that genetic deletion of Malat1 effectively inhibits VEGF mRNA and protein expression in isolated mouse brain microvessels 7 d after ischemic stroke. These findings have provided the basis for our Central Hypothesis that Malat1 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: Examine the functional role of Malat1 in regulating post-stroke angiogenesis; Aim 2: Identify the molecular targets of Malat1 in regulating post-stroke angiogenesis; Aim 3: Determine whether Malat1-mediated angiogenesis affects long-term stroke outcomes. Elucidating the essential role of Malat1 in post-stroke angiogenesis and the underlying mechanism may eventually lead us to identify novel neurorestorative targets for the treatment of ischemic stroke.

大量证据表明，缺血后血管生成有助于改善血液状况 中风的血流和神经系统结果。脑缺血迅速引发多种基因的诱导 以及参与血管生成的蛋白质。增强这些促血管生成因子的干预措施是 缺血性中风后长期功能恢复的有前景的治疗策略。 长链非编码 RNA (lncRNA) 是一类新型非编码 RNA，可调节基因或 蛋白质表达。除了在各种生物过程中发挥关键作用外，lncRNA 还被 与多种人类神经系统疾病有关。我们和其他人最近发现了重要的 lncRNAs在啮齿动物中风模型缺血性损伤发病机制中的作用，表明lncRNAs 潜在的治疗靶点。然而，lncRNAs的功能意义和分子机制 缺血性中风后的血管生成和神经系统结果的晚期阶段尚不清楚。 转移相关肺腺癌转录物 1 (Malat1) 是最早发现的 lncRNA 之一 与人类癌症有关。累积研究表明 Malat1 在多种疾病中发挥着关键作用 病理状况也是如此。此前，我们是第一个发现 (Malat1) 是最受重视的之一。 利用RNA测序技术上调中风反应性内皮lncRNA及其功能障碍 导致急性缺血性脑损伤。我们还证明 Malat1 可以显着抑制细胞- 后肢缺血时的自主血管生成。此外，我们的初步研究表明 Malat1 水平 大脑中动脉术后7天半暗区脑血管显着增加 小鼠大脑中动脉闭塞（MCAO）。值得注意的是，Malat1 基因缺失会导致脑微血管密度降低 MCAO 后 28 天小鼠脑萎缩增加，而 EC 选择性转基因过表达 Malat1 基因增加小鼠缺血后脑血管生成。此外，我们发现遗传 Malat1 缺失有效抑制离体小鼠脑中 VEGF mRNA 和蛋白表达 缺血性中风后7天的微血管。这些发现为我们的中心假设提供了基础 Malat1 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系统结果。该提案将实现三个目标。目的 1：考察Malat1在调节中风后血管生成中的功能作用；目标 2：识别分子 Malat1 调节中风后血管生成的靶标；目标 3：确定 Malat1 是否介导 血管生成影响长期中风结果。阐明 Malat1 在中风后的重要作用 血管生成及其潜在机制可能最终引导我们确定新的神经恢复靶点 用于治疗缺血性中风。