Dissection and manipulation of inflammatory pathways underlying post-traumatic visual outcomes

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Project Summary Blast-mediated traumatic brain injury (bTBI) affects military members and civilians as a direct result of combat, workplace accidents, or intentional terrorist attacks. There are currently no effective pharmacologic therapies for TBI and treatment is limited to supportive care. The retina is a central nervous system (CNS) tissue that is vulnerable to blast exposure. Individuals with blast-mediated TBI often report visual dysfunction, which may manifest months to years after the initial exposure. These problems include light sensitivity, retinopathy, optic neuropathy, dysfunctional optic motility, and visual field loss, although little is known about the molecular changes in both the retina and higher order visual processing centers that lead to visual dysfunction. Following a TBI, secondary signaling cascades occur in the brain, including robust neuroinflammation that exacerbates the initial neuronal insult. Modulating neuroinflammation is a potential therapeutic strategy for treating TBI. The initial inflammatory cascades that occur in the minutes to days following primary tissue injury include interleukin-1 (IL-1) cytokine release. While components of the IL-1 pathway contribute to both CNS repair and secondary injury, overwhelming evidence indicates IL-1 worsens neuronal injury overall after a brain injury. Among members of the IL-1 family, IL-1α and IL-1β increase rapidly after TBI in the brain. The exact role of these cytokines in shaping the neuronal response to TBI is yet unclear, and it is unknown whether modulation of these pathways might prevent neuronal deficits. Furthermore, the role of ocular inflammation and the relative contribution of each IL-1 molecule following TBI has not been systematically explored. My long-term goal is to identify mechanisms of neuroinflammation that contribute to secondary ocular injury and develop novel, targeted therapies. The overall objective of this proposal is to evaluate the role of IL-1 pathway molecules in the retina following blast-mediated TBI. My central hypothesis is that blockade of specific IL-1 pathway molecules following TBI will reduce secondary retinal injury and will be achievable with available anti-IL-1 pathway agents. Understanding the role of individual IL-1 pathway molecules and cellular effectors in the eye following TBI represents a critical knowledge gap. My study may also reveal novel therapeutic approaches that utilize drugs already approved for clinical use. To test my hypothesis, I propose the following Specific Aims: 1) Determine the specific IL-1 pathway molecules that contribute to bTBI pathogenesis in the retina using genetic mouse models and pharmacologic blockade and 2) Determine the role of peripheral cellular effectors contributing to retinal inflammation in bTBI.