TARGETING THE EPIGENOME TO TREAT MTBI

Exposure to blast, bullets and shrapnel, vehicle crashes and falls significantly elevate the risk of traumatic brain injury (TBI) in military personnel. Mild TBI (mTBI) can lead to psychological problems, persistent loss of memory, poor executive functioning and increased risk of dementia. Despite the individual, social and economic burdens of mTBI, no therapies exist to limit the neuronal damage or improve neuroregenerative responses in patients. This proposal addresses this urgent Military Health Care need. We show mTBI invokes dramatic epigenetic effects in the brains of mice. Epigenetic effects are chemical modifications that change the function but not the structure of genes. Epigenetic causes have been identified for a number of neurological disease states and growing evidence indicates epigenetic regulators control innate recovery mechanisms in the brain to trauma and disease. Our data identifies the enzyme Kdm5b as a significant epigenetic regulator of mTBI pathophysiology. We will characterize the function of Kdm5b in mTBI pathophysiology and advance our studies towards clinical application by examining the effects of a small interfering peptide to Kdm5b function. This peptide has been shown to promote the production of neurons from embryonic stem cells. Our prediction is that use of this peptide will promote neuronal replacement during mTBI recovery. We are confident the successful completion of this project will be an important step in the development of epigenetic therapies to treat mTBI.