Profiling the neuroimmune cascade after repetitive mild traumatic brain injury
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Pybus, Alyssa
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Abstract
Mild traumatic brain injury (mTBI) is responsible for about 2 million emergency department visits and an estimated cost burden of $17 billion in the United States every year. Despite its prevalence and cost, current treatment for mTBI is severely lacking and targets symptoms rather than drivers of adverse clinical outcomes. Research into new therapeutic strategies for the treatment of mTBI patients is constrained by our limited understanding of the biological mechanisms behind how brain injury impacts outcomes such as cognitive deficit and neurodegenerative pathology similar to that seen in Alzheimer’s disease. Recent studies unveil new evidence that neuroimmune signaling may be a key driver of long-term outcome after single or repeated mTBI, but there remains an urgent need to identify the specific cellular and molecular pathways involved to assess their potential for targeting in new therapeutic intervention strategies. The work of this dissertation seeks to comprehensively define the neuroimmune response to single and repeated mTBI alongside cognitive and pathological outcome measures to improve our understanding of brain injury and propose potential targets for therapeutic intervention.
The present work uses in vivo murine models of rmTBI to determine the acute effects of injury on neuroimmune signaling in correlation to biomarkers of cognitive and pathological outcome. Our findings in wild type mice suggest that elevated neuroimmune signaling is strongly linked to cognitive outcome. We specifically identified MAPK and NF-κB signaling pathways as strong correlates to biomarkers of outcome and thus promising candidates for therapeutic intervention. Next, we used transgenic mice capable of displaying human-like pathology to relate neuroimmune signaling to pathological outcomes. We identified specific cytokines elevated after injury in correlation to markers of AD-like pathology, suggesting involvement with brain injury-induced pathogenesis and potential for use as diagnostic or prognostic clinical biomarkers. Lastly, our transcriptional profiling revealed rapid neuronal dysfunction within 24 hours after injury followed by changes in astrocyte- and microglia-related gene expression within days.
Taken together, the work of this dissertation defines the protein and transcriptional response to rmTBI alongside cognitive and pathological outcomes to a previously uncharacterized level of detail. Our findings suggest multiple avenues of future work to assess promising therapeutic targets, assess promising diagnostic and/or prognostic TBI biomarkers, fully define the previously underappreciated role of neurons in neuroimmune modulation, and uncover acute drivers of neuroimmune signaling through mechanistic studies.
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2023-07-24
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Dissertation