Background: Elderly individuals are particularly vulnerable to traumatic brain injury (TBI), and numerous studies report clinically worse outcomes in elderly TBI patients. As the aged population continues to grow towards an estimated 71.5 million in 2030 in the US, the burden of TBI in the elderly is expected to dramatically increase, and will have a major impact on the national health care system. Despite these increasing challenges, research on the underlying mechanisms responsible for worse outcomes in elderly TBI patients is limited. Microglial activation is a key secondary injury mechanism that contributes to chronic neurodegeneration and loss of neurological function after TBI. Microglia have multiple activation phenotypes, including a classically activated/M1 state that may to lead to exacerbation of injury and progressive tissue destruction, and an alternatively activated/M2 state that serves to dampen the inflammatory response and promote tissue repair. Whether microglia differentiate into an M1 state that contributes to secondary injury or into an M2 state that promotes repair depends on the signals within the lesion microenvironment (pro- vs. anti- inflammatory), as well as systemic factors;both of which may be influenced by age. Description: The goal of the proposed research is to investigate the underlying molecular mechanisms that contribute to increased microglial activation and associated neurotoxicity in the aged brain following TBI. We hypothesis that increased NADPH oxidase activity during aging tips the M1/M2 microglia balance from favoring an anti-inflammatory M2 state in young, to a pro-inflammatory M1 state in elderly. This shift towards an M1 state will result in increased neurodegeneration and worse neurological outcomes in the elderly. This hypothesis is based on our recently published and preliminary data showing that aged mice have excessive M1 microglial activation in response to TBI compared to young mice, and studies in a knockout mouse which revealed that the polarization of microglia toward an M1 activation state following TBI depends on the activity of a critical molecular switch, NADPH oxidase. Here, we propose to investigate a novel molecular intervention (NADPH oxidase inhibition) to concurrently down-regulate the M1 state and up-regulate the M2 state, and we will determine its potential to promote functional recovery and repair in the young and aged TBI brain.
Specific aims i nclude: 1) Determine if aging alters NADPH oxidase activity and M1/M2-polarization of microglia after TBI, 2) Determine whether NADPH oxidase is a key molecular switch for M1 polarization of microglia after TBI, and 3) Assess whether inhibition of NADPH oxidase will attenuate poorer outcomes in aged TBI mice. Impact: Understanding the molecular mechanisms that polarize microglia towards an M2 state will be crucial to unlock the endogenous potential of microglia to promote repair during the chronic phase of recovery after TBI. Given the impact aging has on neuroinflammation after TBI, targeting NADPH oxidase may be particularly beneficial for the estimated 142,000 elderly individuals that attend the ER each year because of TBI.
The proposed research is relevant to public health because the elderly is the fastest growing patient population that has the worst clinical outcomes after TBI, and the reasons for poorer outcomes in this group are not well understood. If the hypotheses of this proposal are confirmed, then the data from this grant will provide a pathophysiological basis for poorer outcomes in elderly TBI patients, as well as a novel therapeutic intervention that will unlock the endogenous potential of M2-polarized microglia to initiate repair processes during the chronic phase of recovery after TBI.
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