miR-21 induced neuroprotection after stroke

miR-21诱导中风后神经保护

• 批准号: 10513282
• 负责人: Raghu VEMUGANTI
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513282
• 关键词: Adult; Affect; Age; Body Weight decreased; Brain; Brain Injuries; Brain Ischemia; Cause of Death; Cerebral Ischemia; Chemistry; Cognitive; Curiosities; Data; Diabetes Mellitus; Event; Family; Female; Functional disorder; Genes; Goals; Human Resources; Industry; Infarction; Inflammation; Inflammatory; Intravenous; Ischemia; Ischemic Preconditioning; Lead; Mediating; MicroRNAs; Middle Cerebral Artery Occlusion; Mission; Molecular; Motor; Mus; Neurologic Deficit; Neurologic Dysfunctions; Outcome; Patient Care; Peripheral; Pre-Clinical Model; Prevention; Proteins; Quality of life; Reagent; Recovery of Function; Reperfusion Therapy; Rodent; Services; Societies; Stroke; Stroke prevention; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Untranslated RNA; Veterans; Work; comorbidity; disability; dysbiosis; effective therapy; efficacious treatment; efficacy evaluation; functional outcomes; gut dysbiosis; gut inflammation; gut microbiome; improved; improved outcome; male; mortality; motor function recovery; neurological recovery; neuroprotection; neuropsychiatry; novel therapeutics; post stroke; preconditioning; prevent; sex; stroke model; stroke therapy; therapeutic development; therapeutic evaluation

Stroke is a leading cause of death and disability in adult humans including veterans and service personnel. Stroke promotes significant motor, cognitive and neuropsychiatric dysfunction. However, there is no efficacious therapy to prevent post-stroke brain damage and neurologic deficits. Recent studies showed that modulating specific microRNAs (miRNAs) leads to neuroprotection and better functional recovery after stroke in rodents. As the reagents like miRNA mimics and antagomiRs are available to rapidly increase or decrease the levels of a specific miRNA, they became attractive targets for stroke therapeutic development. In preliminary studies, we identified that miR-21 levels increase in a sustained manner when cerebral ischemic tolerance was induced in adult rodents. Preliminary studies also confirmed that miR-21 levels can be increased by >75 fold in mouse brain without any toxicity using a miR-21 mimic. Treatment with miR-21 mimic induced significant neuroprotection and motor function recovery in both male and female mice subjected to transient focal ischemia. In the present proposal, we will rigorously test the therapeutic efficacy of miR-21 in a mouse stroke model following the Stroke Treatment Academic Industry Roundtable (STAIR) stipulated criteria. We will test the hypothesis that miR-21 is a potent neuroprotective miRNA that prevents post-stroke brain damage. In Aim 1, we will evaluate the efficacy of miR-21 mimic in a mouse transient middle cerebral artery occlusion (MCAO) model of stroke. We will test many STAIR criteria including window of therapeutic efficacy, long-term motor, cognitive and neuropsychiatric outcomes, effect of sex, age and diabetes (comorbid condition for stroke) on miR-21 mimic-induced neuroprotection following transient MCAO. We further hypothesize that miR-21 mediated post-stroke neuroprotection is due to prevention of gut microbiome dysbiosis leading to curtailed inflammation. miR-21 targets several pro-inflammatory genes and treatment with miR-21 mimic suppressed some of those in post-ischemic brain. This indicates that miR-21 mediated neuroprotection might be in part due to curtailed post-stroke inflammation. Recent studies showed that gut microbiome influences inflammation in the post- stroke brain. Curiously, miR-21 is a regulator of the gut microbiome. Hence, in Aim 2, we will evaluate if miR- 21 induced neuroprotection is mediated by preventing gut microbiome dysbiosis. The overall goal is to establish miR-21 as a neuroprotective miRNA with potential to decrease post-stroke brain damage and improve functional recovery by rectifying gut dysbiosis and inflammation. If successful, these studies leads to establishment of miR-21 as a new therapy to help service personnel and veterans who suffer a stroke. Relevance of the proposed work to the VA patient care mission: Every year, ~15,000 US veterans suffer a stroke and many of those who survive struggle with long-term functional deficits. The negative impact of this devastating condition on veterans is enormous for the families as well as society in terms of financial loss and quality of life. Successful completion of the proposed studies to identify if miR-21 mimic treatment leads to better recovery of functions in surviving stroke sufferers will be enormously helpful to veterans.

中风是包括退伍军人和服役人员在内的成年人死亡和残疾的主要原因。 中风会导致显着的运动、认知和神经精神功能障碍。然而目前还没有特效药 预防中风后脑损伤和神经功能缺损的治疗。最近的研究表明，调节 特定的 microRNA (miRNA) 可以在啮齿动物中提供神经保护和中风后更好的功能恢复。 由于 miRNA 模拟物和 antagomiR 等试剂可快速增加或减少 作为一种特定的 miRNA，它们成为中风治疗开发的有吸引力的靶标。在初步研究中，我们 发现当诱导脑缺血耐受时，miR-21 水平持续增加 成年啮齿动物。初步研究还证实，小鼠体内的 miR-21 水平可增加 >75 倍 使用 miR-21 模拟物对大脑进行无任何毒性的研究。 miR-21模拟物治疗诱导显着 短暂性局灶性损伤的雄性和雌性小鼠的神经保护和运动功能恢复 缺血。在本提案中，我们将严格测试 miR-21 对小鼠中风的治疗效果 模型遵循中风治疗学术行业圆桌会议 (STAIR) 规定的标准。 我们将检验以下假设：miR-21 是一种有效的神经保护 miRNA，可预防中风后大脑 损害。在目标 1 中，我们将评估 miR-21 模拟物在小鼠短暂大脑中动脉中的功效 中风闭塞（MCAO）模型。我们将测试许多 STAIR 标准，包括治疗功效窗口、 长期运动、认知和神经精神结果，性别、年龄和糖尿病的影响（合并症） 中风）对短暂 MCAO 后 miR-21 模拟物诱导的神经保护作用。 我们进一步假设 miR-21 介导的中风后神经保护是由于预防肠道损伤 微生物群失调导致炎症减少。 miR-21 靶向多种促炎症基因，用 miR-21 模拟物治疗可抑制其中的一些基因 脑缺血后。这表明 miR-21 介导的神经保护作用可能部分归因于抑制 中风后炎症。最近的研究表明，肠道微生物群会影响术后炎症。 中风大脑。奇怪的是，miR-21 是肠道微生物组的调节因子。因此，在目标 2 中，我们将评估 miR- 21 诱导的神经保护作用是通过预防肠道微生物群失调来介导的。 总体目标是将 miR-21 建立为一种神经保护 miRNA，具有减少中风后脑损伤的潜力 通过纠正肠道菌群失调和炎症来减轻损伤并改善功能恢复。如果成功的话，这些 研究导致建立 miR-21 作为一种新疗法，以帮助遭受疾病困扰的服役人员和退伍军人 中风。 拟议工作与 VA 患者护理任务的相关性：每年，约有 15,000 名美国退伍军人遭受 中风和许多幸存者都在与长期的功能缺陷作斗争。此举带来的负面影响 退伍军人的毁灭性状况对家庭和社会造成巨大的经济损失和 生活质量。成功完成拟议的研究，以确定 miR-21 模拟治疗是否会导致 幸存的中风患者更好地恢复功能将对退伍军人有很大帮助。