Contributions of Astrocyte RelA Signaling in Aging-Related Neurodegenerative Sequelae Following TBI

Abstract: This proposal will mechanistically examine the role of RelA as a causal mechanism underlying dystrophic of aged astrocytes following traumatic brain injury (TBI). Recent epidemiological data show that age is a significant risk factor for acquired brain injury, which clinically, aged individuals have strikingly increased morbidity and mortality following TBI, compared to younger individuals. Those aged individuals that do survive the initial trauma suffer from decreased functional recovery as well. Increasing evidence has begun to emerge that astrocytes play a critical role in signaling cascades linked maintaining homeostasis in the brain following trauma or disease states, yet little is known regarding manipulating astrocyte-specific mechanism that may underlie a dysfunction pathophysiological role they may acquire. This proposal will mechanistically determine if RelA is a critical signaling mediator propagating a maladaptive phenotype of a subset of astrocytes that are present in the aged brain following trauma. We will pursue three specific aims to interrogate the cell-specific heterogeneity of astrocytes, their contribution to aberrant neuroinflammatory sequelae, as well as their functional role in synaptic transmission, function, and cognitive outcomes in the aged brain following TBI and whether deleting RelA mitigates these degenerative sequelae.