The overall goal of this project is to determine whether TBI-induced inflammatory changes result in peripheral organ damage that is dependent on activation of the inflammasome by extracellular vesicles (EV) and ASC specks. Our recent work has shown that a crucial part of the TBI-induced systemic inflammatory response involves release of extracellular vesicles containing a cargo of innate immune proteins that are secreted from damaged central nervous system (CNS) tissue. Importantly, EV and ASC specks from TBI animals induce inflammasome activation in peripheral organs.
The specific aims of this proposal will determine the cellular and molecular mechanisms regulating EV- and ASC speck-mediated innate immune inflammatory reactions in peripheral organs after TBI. The hypothesis of this study is that EV and ASC specks play a central role in innate immune signaling by carrying inflammasome proteins to peripheral organs after TBI, thus causing tissue injury. Moreover, neutralization of secreted ASC with a monoclonal antibody decreases peripheral organ damage after TBI, resulting in improved histopathological outcomes.
Aim 1 will determine if TBI alters the composition of EV proteins in brain, peripheral organs and bodily fluids. These studies will delineate a protein profile of EV proteins after TBI.
Aim 2 will establish if ASC specks accumulate in brain and peripheral organs after TBI and induce an inflammatory responses leading to pyroptosis. We will investigate whether the activation of inflammasomes in vivo leads to the appearance of ASC specks and whether the deposition of ASC specks in tissues induces the recruitment of neutrophils and lymphocytes, thus contributing to the inflammatory milieu in peripheral organs.
Aim 3 will determine the therapeutic effects of antibody neutralization of the inflammasome on histopathological outcomes after TBI. These studies will provide critical information about the activation patterns of innate immunity regulated by EV and ASC specks in the CNS, and identify relevant therapeutic targets to control inflammation following TBI and other neurodegenerative disorders.
Brain injury is the leading cause of death and disability worldwide. Motor Vehicle Crashes account for 50% of all TBIs. The leading causes of TBI vary by age: falls are the leading cause of TBI among persons aged 65 years and older; transportation is the leading cause of TBI among persons under the age of 65 years. Estimates suggest that sports-related brain injury accounts for close to 300,000 injuries each year. Currently, there are no established successful therapies treating acute TBI and there is a critical need to develop new strategies for assessing injury severity as well as guiding therapeutic interventions. The proposed research seeks to reduce cell death by inflammation that occurs in the brain and peripheral organs within days of TBI, and to devise therapies to treat TBI-related comorbidities and help in long-term recovery of function. The development of new treatments that can be given in the first hours after TBI may prevent or reverse much of the brain and peripheral organ damage resulting from TBI with a goal of restoring normal function and behavior.