The effect of extracranial trauma and age on traumatic brain injury, and the role of neuroinflammation
Document TypePhD thesis
Access StatusOpen Access
© 2018 Dr. Mujun Sun
Traumatic brain injury (TBI) is induced by external forces to the brain, and is a leading cause of mortality and morbidity worldwide. Although significant research efforts have been made to identify an effective treatment, all phase III clinical trials have been unsuccessful to date. These translational shortcomings are in part due to a failure to recognize and account for the heterogeneity of TBI. TBI is often not an isolated injury; yet the majority of preclinical research has utilized isolated TBI models, and how concomitant extracranial factors, such as extracranial trauma and aging, might inﬂuence TBI is still largely unknown. Extracranial trauma or aging involve a significant immune response, which is also a pathological hallmark of TBI. As such, this research project aims to study how these extracranial immunological stressors have potential to affect TBI and how this might inﬂuence future treatment strategies. The first study found that a concomitant bone fracture exacerbated neuroinflammation and other TBI-related pathological events in mice, with the pro-inflammatory cytokine interleukin (IL)-1 being robustly upregulated. The consequent study suggested that treatment with an IL-1 receptor antagonist improved neurological outcomes in the combined TBI + fracture model. While a long-bone fracture exacerbates TBI outcomes in mice, the third study in this thesis found that a concomitant muscle injury did not. The final study investigated the effect of aging on TBI, and found that middle-aged rats had an altered neuroimmune response and worse functional outcomes after TBI compared to young rats. Together, this body of work generates significant new knowledge about the fundamental mechanisms by which extracranial variables such as peripheral injuries and biological age influence the neuropathological outcomes after neurotrauma.
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- Medicine (RMH) - Theses