Precision Medicine Approach: Using genomic information to guide TBI treatment

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ABSTRACT Concussive injury or mild/moderate TBI (mTBI) accounts for a large majority of the brain injuries in USA and compromises neuronal function and cognitive abilities. The main premise of the parent grant is that gene regulatory programs determine cellular functions such that scrutiny of large-scale genomic changes can reveal clues to the molecular determinants of mTBI pathogenesis, including disease predisposition. Studies outlined in the award are directed to use genomic analysis in cells as a tool to provide leads to the TBI pathology and guide the discovery of therapeutic targets. We found that the receptor for thyroid hormone transporter in the brain is a potential target for therapeutic interventions. Therefore, an important goal of the project is to investigate the potential of thyroid hormone to be used as a therapeutic agent. We posit to examine the possibility that thyroid hormone T4 treatment can activate gene regulatory mechanisms that control functionality of circuits in brain regions important for processing of higher order information. Studies involved in the supplement (not included in the parent grant) are directed to complement information about the action of T4 treatment to reduce the pathology of TBI. Since a large aspect of T4 metabolism occurs in the body, we will determine how the action of thyroid hormone in the periphery can modulate central mechanisms in areas associated with processing of cognitive function such as the hippocampus and hypothalamus. Indeed, T4 is metabolized in the liver before reaching the brain and the peripheral pathology of TBI can contribute to modulate the brain pathology. Dr. Mercado will conduct research directed to determine how the metabolism of T4 in the periphery influences the TBI pathogenesis in the brain, according to the scope of the parent grant. Given that a large portion of brain lipids are metabolized in liver, we will assess the possibility that liver lipids can be a vehicle for the periphery to influence TBI on brain function and behavior. Dr. Mercado will be trained in a myriad of new concepts and techniques in the field of TBI. In addition, Dr. Mercado will be exposed to the elite neuroscience community at UCLA and will participate in organized training programs for young investigators on the path to an independent academic career.