Brain, Behavioral, and Mental Health Research Career Scientist Award Application

About This Grant

Ischemic stroke and traumatic brain injury (TBI) are major causes of mortality and long-term functional deficits in veterans and service personnel. Dr. Vemuganti’s current research is to identify new molecular targets to develop therapies for protecting the brain and promote the functional recovery following stroke and TBI. Although stroke is #1 cause of disability in adults, there is no efficacious therapy to prevent post- stroke brain damage and functional deficits. Several classes of noncoding RNAs such as microRNAs (miRNAs) and long noncoding RNAs are known to modulate the post-stroke brain damage. Dr. Vemuganti’s currently funded Merit Review Grant is evaluating if a miRNA known as miR-21 upregulated after stroke can potentially target the mRNAs that promote inflammation, oxidative stress and apoptosis. The project is specifically evaluating if treatment with a miR-21 mimic protects the brain and promotes better motor, neuropsychiatric and cognitive functional recovery after stroke induced by transient middle cerebral artery occlusion (MCAO) in mice of both sexes. The proposal is comprehensively testing the efficacy of miR-21 mimic in modulating long-term outcomes as a function of sex, age and comorbid conditions. Recent studies showed that gut microbiome influences neuroinflammation and other pathologic events after stroke. Hence, the project is also testing if miR- 21 mediated post-stroke neuroprotection is due to prevention of gut microbiome dysbiosis leading to better outcomes. The overall goal is to test the therapeutic potential of miR-21 to translate further to human studies. If successful, these studies lead to establishment of miR-21 as a new therapy to help service personnel and veterans who suffer a stroke. TBI promotes significant motor, cognitive and neuropsychiatric dysfunction. The effects of TBI in surviving veterans can often be seen for decades after the initial injury. Vitamin C (ascorbate) is highly concentrated in brain and known to promote neuroprotection after acute and chronic CNS insults. However, its efficacy in TBI was not yet tested comprehensively. In a VA funded Merit Review Grant, Dr. Vemuganti’s lab is testing the efficacy of ascorbate treatment in reducing the secondary brain damage and promoting better motor and cognitive functional outcome in adult mice subjected to controlled cortical impact-induced TBI. Epigenetic changes are known to significantly influence the gene expression and outcome after TBI. Of particular interest, hydroxymethylation of cytosine in DNA catalyzed by TET hydroxylases forms 5-hydroxymethylcytosine (5hmC), which is a transcriptional de- repression mark that increases cell survival under adverse conditions. As brain contains ~10-fold higher 5hmC levels than other organs of the body, we are testing if ascorbate treatment enhances cerebral TET activity and 5hmC levels after TBI and if this epigenetic modification is a major mechanism of ascorbate-induced neuroprotection after TBI. The long-term goal is to provide a therapy to help service personnel and veterans who suffer a TBI.