BLRD Research Career Scientist Award Application

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Dr. Vemuganti’s current research is to find therapies for preventing secondary brain damage and to promote neurological recovery following either traumatic brain injury (TBI) or ischemic stroke. TBI and stroke are leading causes of disability in service personnel and Veterans and they suffer the effects of these for decades after the initial events. Oxidative stress and endoplasmic reticulum (ER) stress that starts within hours and continues for days promotes neuronal death that lead to long-term neurological deficits after TBI. Hence, the currently funded Merit Review Grant of Dr. Vemuganti will test the hypothesis that an antioxidant combination therapy (to prevent the formation of ROS and induce the disposal of ROS) protects the brain and promotes long-term functional gains in both sexes at different ages after TBI. We further test the hypothesis that preventing oxidative stress and ER stress together is more efficacious to protect the brain and to promote neurological recovery after TBI. We will also test the hypothesis that controlling oxidative stress decreases the propensity of Parkinson’s disease (PD) pathology after TBI. The studies will use a well-developed mouse model of TBI known as controlled cortical impact injury. Motor function, cognitive function and neuropsychiatric function will be studied as well as cortical contusion in mice subjected to TBI and treated with the combo therapies. Overall, the present project will help us to find a drug combo that minimizes secondary brain damage and neurologic dysfunction after TBI by curtailing oxidative stress and ER stress after TBI. The long-term goal is to provide a therapy to help service personnel and Veterans who suffer a TBI. 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. The miRNA miR-21 is anti-apoptotic and anti-inflammatory. We observed that miR-21 levels in the brain increases by treatment with a miR-21 mimic without any toxicity. Hence, in a Merit Review Grant that is currently pending, Dr. Vemuganti will test the hypothesis that miR-21 mimic is a potent neuroprotective therapy to prevent post-stroke brain damage using a mouse stroke model called transient middle cerebral artery occlusion (MCAO). Stroke Treatment Academic Industry Roundtable (STAIR) stipulated many criteria for testing new therapies. Following those, we will test the 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. Recent studies showed that gut microbiome influences inflammation in the post-stroke brain. Hence, we will further test the hypothesis that miR-21 mediated post-stroke neuroprotection is due to prevention of gut microbiome dysbiosis leading to curtailed inflammation. 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.