Traumatic brain injury (TBI) is a leading cause of mortality and long-term disability worldwide. Over 1.7 million Americans suffer a TBI annually and up to 2% of the population currently lives with the long-term neurological consequences of a previous TBI, placing a $76.5 billion annual economic burden on society. Preventative measures reduce injury incidence and/or severity, yet one-third of hospitalized TBI patients die from injuries that are secondary to the initial trauma. Cerebral edema is a life-threatening neurological complication that promotes elevated ICP and leads to clinical deterioration in the hours and days after a TBI. Unfortunately, neurosurgical approaches to control elevated ICP are limited and efficacious medical therapies to control cerebral edema are lacking. A critical barrier to improving patient prognoses remains a lack of clinically effective treatment options after TBI. The objective of this proposal is to implicate NLRP3 as a functional mediator of neurovascular injury after TBI.
Specific Aim 1 will test the hypothesis that P2X7 promotes NLRP3 inflammasome activation after TBI.
Specific Aim 2 will test the hypothesis that inhibition of the NLRP3 inflammasome attenuates neurological injury after TBI. Expected outcomes of the proposed research include: (1) identification of P2X7 as a key mediator of NLRP3 inflammasome formation following TBI, and (2) demonstration that NLRP3 promotes cerebral edema and worsens neurological outcomes after TBI. These studies may have far-reaching translational implications as the identification of NLRP3 as a key mediator of secondary injury will provide a novel target for therapeutic intervention. These studies also will provide a mechanism of action whereby two-clinically useful therapeutics control post-traumatic edema, providing rationale for rapid clinical translational of these findings after TBI. !
Traumatic brain injury (TBI), a leading cause of mortality and long-term disability worldwide, is a significant public health issue, debilitating or killing more individuals that breast cancer, AIDS, multiple sclerosis, and spinal cord injury combined. Brain swelling is a life-threatening neurological complication that develops in the hours and days after the trauma and results in worse outcomes. Unfortunately, treatment options to limit or reverse brain swelling are limited, representing a critical barrier to improving patient prognosis. This application will use genetic and drug-targeting approaches to identify a protein complex called the NLRP3 inflammasome in causing the brain to swell in a pre-clinical model of TBI. We will also explore the efficacy and mechanism of action for two FDA-approved compounds to reduce brain swelling. If successful, the findings from the project can be directly and immediately translated in clinical practice to improve patient outcomes after TBI. Relevance to human health: TBI is a major cause of death and disability across gender and age demographics. Elucidating a novel mechanism of brain swelling may provide a target for future drug development. These studies will also provide rationale for advancing two FDA-approved compounds into clinical trials for head trauma patients.
|Laird, Melissa D; Shields, Jessica S; Sukumari-Ramesh, Sangeetha et al. (2014) High mobility group box protein-1 promotes cerebral edema after traumatic brain injury via activation of toll-like receptor 4. Glia 62:26-38|