miR-21 induced neuroprotection after stroke

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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.