Identification and validation of target pathways influencing outcome after traumatic brain injury

Ferguson, Scott Allen (2012). Identification and validation of target pathways influencing outcome after traumatic brain injury. PhD thesis The Open University.



Traumatic brain injury (TBI) involves both an initial primary insult to the brain and a delayed secondary injury in the hours and days thereafter. The delayed nature of secondary brain injury leaves open the possibility for a window of therapeutic intervention to prevent neurodegeneration. As there are currently no approved drugs for the treatment and prevention of secondary injury after TBI, my approach has been to first identify molecular pathways associated with a differential outcome from injury, followed by validation of these pathways by targeting them with a variety of therapeutic strategies ranging from genetic manipulation to novel drug compounds, and dietary supplementation. The Apolipoprotein E (APOE) gene has three major alleles, APOE2, APOE3 and APOE4, the latter of which confers risk for poor outcome following TBI. Using quantitative Liquid Chromatography-Mass Spectrometry, large proteomic datasets can be generated, and the difference in protein expression in response to TBI between transgenic mice expressing APOE3 or APOE4 can reveal changes that reflect a "better" or "worse" outcome, respectively. Analyzing such datasets from APOE3 and APOE4 transgenic mice at a wide range of time points, we examined the differential response to TBI and identified several protein pathways of interest, including: CD40 signaling, NF-kB signaling, and APP related proteins. Optimizing several behavioral I testing paradigms (Rotarod, Morris Water Maze, and Barnes Maze), we characterized spatial memory and motor function deficits resulting from TBI in order to quantify a "good" or "poor" response. Using a variety of targeted intervention strategies (CD40L knockout, administration of (-)-Nllvadipine, or anatabine) to modulate the protein pathways of interest, we showed improvement in response to TBI. Overall, these experiments provide demonstrate the effectiveness of using a systems biology approach to find potential targets for therapeutic intervention.

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