miR-21 induced neuroprotection after stroke

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。 中风会导致严重的运动、认知和神经精神障碍。然而，没有灵丹妙药。 预防中风后脑损伤和神经功能障碍的治疗。最近的研究表明，调制 特定的microRNAs(MiRNAs)对啮齿动物卒中后的神经保护和更好的功能恢复起到了作用。 随着miRNA模拟物和反交配子等试剂的出现，可以迅速增加或降低 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点。在初步研究中，我们 在诱导脑缺血耐受时，miR-21水平持续升高。 成年啮齿动物。初步研究还证实，miR-21在小鼠体内的水平可以增加75倍 大脑没有任何毒性，使用了miR-21模拟物。MiR-21模拟细胞的治疗作用显著 短暂性局灶性脑损伤雌雄小鼠的神经保护和运动功能恢复 缺血症。在目前的提案中，我们将严格测试miR-21在小鼠中风中的治疗效果。 模型遵循中风治疗学术行业圆桌会议(STAIR)规定的标准。 我们将验证miR-21是一种有效的神经保护miRNA的假设，它可以预防中风后的大脑 损坏。在目标1中，我们将评估miR-21模拟物在小鼠暂时性大脑中动脉中的作用。 卒中闭塞(MCAO)模型。我们将测试包括疗效窗在内的许多阶梯标准， 长期运动、认知和神经精神结果、性别、年龄和糖尿病的影响(并存情况 中风)对短暂性大脑中动脉阻塞后miR-21模拟诱导的神经保护作用。 我们进一步假设miR-21介导的卒中后神经保护是由于肠道的预防 微生物群失调导致炎症减少。 MiR-21针对几个促炎基因，而miR-21模拟治疗抑制了其中一些基因 脑缺血后。这表明miR-21介导的神经保护可能在一定程度上是由于抑制 中风后发炎。最近的研究表明，肠道微生物群影响创伤后的炎症反应。 中风的大脑。奇怪的是，miR-21是肠道微生物群的调节器。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防止肠道微生物群失调来实现的。 总体目标是建立miR-21作为神经保护性miRNA，具有降低中风后脑损伤的潜力 通过纠正肠道生物失调和炎症，损害和改善功能恢复。如果成功，这些 研究导致建立miR-21作为一种新的治疗方法，以帮助遭受 卒中。 拟议工作与退伍军人管理局患者护理任务的相关性：每年，约15,000名美国退伍军人遭受 中风和许多幸存下来的人都在与长期的功能缺陷作斗争。这件事的负面影响 退伍军人的毁灭性状况对家庭和社会来说都是巨大的经济损失和 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。

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.