Thursday, November 21, 2024
11/21/2024
Abstract Traumatic brain injury (TBI) affects millions of otherwise healthy individuals annually. A significant risk factor for TBI is alcohol intoxication, with 30-50% of TBI cases in the US attributed to alcohol-intoxication at the time of injury, potentially intensifying cognitive deficits and TBI-related disability, particularly in moderate to severe cases. Moreover, following TBI, approximately 25% of TBI patients resume alcohol consumption, which can also contribute to neuropathological outcomes. Several mechanisms can contribute to greater injury in alcohol and TBI comorbid conditions. Prior work from our laboratory has shown enhanced neuroinflammation at site of TBI in rodents exposed to alcohol, and delayed recovery of neurobehavioral function in TBI followed by alcohol exposure. Enhanced neuroinflammation may be the result of mitochondrial components or metabolic byproducts that act as damage-associated molecular patterns (DAMPs). Alcohol and TBI both alter cellular metabolism, affects mitochondrial function and glutathione availability. The TBI and alcohol associated disruption in brain metabolism, requires metabolic flexibility in energy substrate utilization to maintain adequate ATP production. This metabolic shift may lead to glutathione depletion and reactive oxygen species overproduction, triggering cell death and accentuated neuropathology that can significantly impact recovery from TBI. Based on these data, we hypothesize that alcohol exacerbates TBI-induced alterations in mitochondrial bioenergetics; particularly at the site of injury, leading to increased oxidative stress and cell death. Ferroptosis, an iron-dependent programmed cell death mechanism, is highly sensitive to mitochondrial bioenergetic alterations and is reported in TBI. The research-training plan proposes three specific aims to test the hypothesis that a) alcohol impairs mitochondrial bioenergetics at the site of TBI injury, b) alcohol accentuates oxidative stress affecting predominantly astrocytes at the site of TBI, c) and that ferroptosis is a significant contributor to cell death at the TBI site. The applicant will leverage his background training in mitochondrial mechanisms of tissue injury, translating them from cardiac tissue to the brain and from ischemic injury to TBI, with emphasis of the role of alcohol in exacerbating these pathophysiological mechanisms.
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