Chronic Traumatic Encephalopathy (CTE) is a progressive neurodegenerative disease triggered by Repetitive Head Impact (RHI). Individuals who experience RHI/concussions while playing high-contact sports (e.g. Rugby, American Football) are at increased risk of developing CTE and related neurobehavioral and cognitive deficits later in life. While traditionally defined by post-mortem tau pathology, recent evidence suggests that upstream molecular mechanisms drive neuronal loss prior to protein aggregation. Crucially, studies on acute Traumatic Brain Injury (TBI) have identified a “secondary injury” cascade characterised by oligodendroglial innate immune activation and susceptibility to oxidative stress/damage (Garza et al., 2023). Concurrently, recent genomic findings (Dong et al., 2025) have revealed that CTE neurons exacerbate somatic mutations and DNA damage similar to Alzheimer’s disease (AD), and this coexists with inflammatory changes in microglia, oligodendroglia, and endothelial cells in confirmed CTE cases (Butler et al., 2025). Using available transcriptomic data from control, RHI, and CTE subjects, along with advanced bioinformatics methods, my HRB summer research project tests the novel hypothesis that persistent glial activation/oxidative stress, originating from acute TBI, drives neuronal genomic damage in CTE.
Using a comparative multi-omic bioinformatic methodology, I will integrate single-nucleus transcriptomics (snRNA-seq) from acute TBI and chronic RHI/CTE cohorts with external single-cell genomic datasets. By mapping data with R (Seurat) and other pathway analysis applications, I will bioinformatically investigate whether dysregulated oxidative pathways (e.g. NOX2/ROS/NLRP3) in oligodendroglia/microglia are related to the burden of somatic mutations in excitatory neurons. This research seeks to uncover the neuroimmune mechanistic link bridging concussion/TBI to genetic instability in neurons that precede CTE and neurobehavioral changes in athletes, identifying novel therapeutic targets to prevent neurodegeneration in concussion/TBI.