Investigating and treating metabolic deficits in the neurovascular unit following mild traumatic brain injury

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Traumatic brain injuries (TBIs) are a major societal and public health concern with over 1.7 million TBIs, ~80% of which mild, are reported each year in the US. TBI is also a major risk factor for dementias and Alzheimer’s Disease. Mild TBI is characterized by dysfunction of the neurovascular unit (NVU), initiated by breakdown of the blood-brain barrier and followed by synaptic dyshomeostasis. Mitochondrial dysfunction is apparent in the NVU after mild TBI, accompanied by metabolic imbalance and oxidative damage. This project will examine the metabolic deficits of distinct components of the NVU, including neuronal synapse and brain capillaries, by using steady state metabolomics as well as intra-mitochondrial metabolic tracing following mild TBI. These results will be generated in conjunction with profiling of mitochondrial bioenergetics of the NVU components. These studies will directly use the resources provided by the CNS-Met Metabolomics Core. P7C3- A20, which elevates NAD+ and demonstrates efficacy in TBI models, will be administered alongside nicotinamide mononucleotide, which is a NAD+ precursor, to examine therapeutic effect at restoring alterations in metabolism and functional outcomes. The completion of these studies will generate an enhanced understanding of mitochondrial dysfunction and metabolite flux in distinct components of the NVU following mild TBI and provide supportive data on a pathology-modifying drugs targeting NAD+ to treat this disease.