MicroRNA210 and neuroinflammation in acute brain injury of ischemic Stroke

MicroRNA210与缺血性中风急性脑损伤中的神经炎症

• 批准号: 10579511
• 负责人: Qingyi Ma
• 金额: $ 44.34万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10579511
• 关键词: Acute; Acute Brain Injuries; Automobile Driving; Bioenergetics; Biological Markers; Brain; Brain Hypoxia-Ischemia; Brain Infarction; Brain Injuries; Cells; Clinical; Coagulation Process; Complex; Data; Development; Disabled Persons; Disease; Electron Transport; Epigenetic Process; Event; Excision; Functional disorder; Genes; Glucose; Glycolysis; Health; Health Care Costs; Hypoxia; Inflammatory; Inflammatory Response; Interleukin-1; Investigation; Ischemic Brain Injury; Ischemic Stroke; Knock-out; Link; Macrophage; Measures; Mediating; Metabolic; Microglia; Mitochondria; Molecular; Morbidity - disease rate; Mus; Neuronal Injury; Oligonucleotides; Outcome Study; Oxidative Phosphorylation; Oxidative Stress; Oxygen; Pathway interactions; Patients; Phenotype; Play; Proteins; Public Health; Research; Respiration; Role; Series; Severities; Stroke; Sulofenur; Testing; Therapeutic; Transfection; United States; Vision; cell type; complex IV; cytokine; deprivation; effective therapy; experimental study; glial activation; innovation; insight; locked nucleic acid; mitochondrial dysfunction; mitochondrial metabolism; mortality; neuroinflammation; neurotoxicity; normoxia; novel; post stroke; response; therapeutic target; therapeutically effective; thrombolysis; transcriptome

PROJECT SUMMARY lschemic stroke is the major type of stroke with high mortality and morbidity, and the health care costs are exorbitant and result in a significant societal burden. Currently although limited therapies including thrombolysis and endovascular clot removal have been approved for the treatment of acute ischemic brain injury, many patients still die or remain disabled. Underlying mechanisms remain poorly understood, hindering the development of effective and specific treatments for this health concern. Thus, there is an urgent need to further investigate the molecular mechanisms and identify effective therapeutic targets. Neuroinflammation is a critical contributor to the pathophysiology of acute ischemic brain injury, in which microglial activation plays a central role. We have recently discovered that microRNA210 (miR210) inhibition significantly reduced brain microglial activation and inflammatory response post-stroke in mice. Our preliminary data also showed miR210 mimic transfection upregulated pro-inflammatory cytokine in primary microglia, and miR210 inhibition reduced the expression of pro-inflammatory cytokine IL-1 f3 after oxygen-glucose deprivation (OGD). These findings suggest a new mechanism of miR210 in microglial inflammatory response contributing to ischemic brain injury. The mitochondria are a major target of miR210 during hypoxia and reprogramming of mitochondrial metabolic switch from oxidative phosphorylation to glycolysis contributes to pro-inflammatory microglial activation. We and others have demonstrated that miR210 reduces mitochondrial oxidative phosphorylation by negatively regulating a number of electron transport chain (ETC)-related genes in multiple cells and increases mitochondrial dysfunction. However, whether miR210 promotes metabolic shift in hypoxic mitochondrial respiration in favor of glycolysis and drives pro-inflammatory microglial response in the setting of stroke is unknown and requires further investigation. Thus, this proposal will attempt to reveal the mechanistic links of metabolic reprogramming in miR210-mediated pro-inflammatory microglial activation in ischemic brain injury. We will evaluate the mechanism of miR210-mediated mitochondrial metabolic shift in programming of proinflammatory microglia and neurotoxicity. We will also determine whether and to what extent miR210 deficiency inhibits microglial mitochondrial dysfunction and reduces neuroinflammation after acute ischemic brain injury. We expect to generate unique insights into the novel role of epigenetic mechanism in the activation of microglial pro-inflammatory phenotype through metabolic shift in the brain post-stroke. The outcome of this study will delineate the mechanism of miR210 in driving microglial inflammatory response. It represents a major breakthrough and paradigm-shifting focus of research and will provide new visions into a novel target of miR210 in potential therapeutic strategies for acute ischemic brain injury.

项目摘要 缺血性脑卒中是脑卒中的主要类型，具有较高的死亡率和发病率， 这是一个巨大的社会负担，并造成巨大的社会负担。目前，虽然有限的治疗方法， 血栓溶解和血管内凝块清除已被批准用于治疗急性缺血性脑 受伤后，许多患者仍然死亡或残疾。基本机制仍然知之甚少，阻碍了 为这种健康问题开发有效和具体的治疗方法。因此，迫切需要 进一步研究分子机制并确定有效的治疗靶点。神经炎症是一种 在急性缺血性脑损伤的病理生理学中，小胶质细胞活化起着重要的作用。 中心角色。我们最近发现，microRNA 210（miR 210）抑制显著降低了大脑 小胶质细胞活化和小鼠中风后的炎症反应。我们的初步数据也显示miR 210 模拟转染上调了原代小胶质细胞中的促炎细胞因子，并且降低了miR 210抑制 氧糖剥夺（OGD）后促炎细胞因子IL-1 f3的表达。这些发现 提示miR 210在导致缺血性脑损伤的小胶质细胞炎症反应中的新机制。 线粒体是miR 210在缺氧和线粒体重编程过程中的主要靶点。 从氧化磷酸化到糖酵解的代谢转换有助于促炎性小胶质细胞 activation.我们和其他人已经证明，miR 210通过以下方式减少线粒体氧化磷酸化： 负调节多个细胞中的电子传递链（ETC）相关基因的数量， 线粒体功能障碍然而，miR 210是否促进缺氧线粒体中的代谢转变， 呼吸有利于糖酵解和驱动促炎性小胶质细胞反应，在中风的设置， 未知，需要进一步调查。因此，这一建议将试图揭示的机械联系， 缺血性脑损伤中miR 210介导的促炎性小胶质细胞活化的代谢重编程。 我们将评估miR 210介导的线粒体代谢转变在促炎性细胞因子编程中的机制。 小胶质细胞和神经毒性。我们还将确定miR 210是否以及在多大程度上 缺乏抑制小胶质细胞线粒体功能障碍并减少急性缺血后的神经炎症 脑损伤我们希望能对表观遗传机制在遗传学中的新作用产生独特的见解。 通过中风后大脑中的代谢转变激活小胶质细胞促炎表型。的 本研究的结果将描述miR 210驱动小胶质细胞炎症反应的机制。它 代表了一个重大的突破和范式转移的研究重点，并将提供新的视野， miR 210在急性缺血性脑损伤的潜在治疗策略中的新靶点。