Blood- brain barrier integrity plays a central role in protecting the brain from the potentially neurotoxic effect of circulating metabolites in the blood. This research proposal seeks to identify the impact of blood brain barrier breakdown on acute irreversible striatal injury, the hallmark of glutaric aciduria type 1 (GA-1). Individuals affected by this inborn error in metabolism have increased serum and tissue levels of glutaric acid and 3-OH glutaric acid due to the inability to metabolize the essential amino acid lysine. This proposal will utilize our established animal model of GA-1 encephalopathy to determine 1) the role of blood brain barrier disruption in precipitating the striatal injury, 2) the impact of inflammation on blood brain barrier integrity and irreversible striatal injury and 3) efficacy of therapeutic interventions aimed at preserving the blood brain barrier integrity and preventing striatal injury. We will utilize high-resolution magnetic resonance imaging to monitor BBB integrity and the onset of striatal injury. The results of the proposed experiments will have three-fold impact. First, the magnetic resonance imaging is already clinically used to monitor changes following ischemic brain injury, and proposed imaging strategy can be directly translated to clinical practice. The results of proposed experiments will serve to develop better assessment and prediction of affected GA-1 children at risk before devastating striatal injury takes place. Second, we hope to begin to uncover the role of inflammation in precipitating the striatal injury, and contribute toward our understanding of the mechanism behind the selective neuronal loss in this devastating disease. Third, the proposed therapeutic strategy may prove promising for future therapeutic interventions.
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