Immunosenescence and Mitochondrial Bioenergetics in Spinal Cord Injury

The purpose of this grant is to study the effects of age-dependent mitochondrial dysfunction on spinal cord injury (SCI) inflammation, secondary injury processes, and recovery. Specifically we hypothesize that age-induced mitochondrial dysfunction contributes to oxidative damage and modifies microglia/macrophage activation after SCI. Our hypothesis is based upon four key observations: 1) Baseline mitochondrial bioenergetics are disrupted with age leading to >2 fold increase in mitochondrial ROS production in the uninjured spinal cord (14 vs. 4 month old (MO) rodents). 2) ROS-mediated oxidative damage is significantly increased after aged vs. young SCI mice. 3) The balance of pathological and pro-reparative, SCI macrophages is disrupted with age. 4) Age disproportionally increases ROS production in pro-reparative SCI macrophages. We propose two specific aims with rationale for this approach below. Aim 1: Determine the effect of age on SCI macrophage mitochondrial function. We hypothesize that age potentiates mitochondrial dysfunction coincident with imbalanced activation of pathological vs. beneficial macrophages after SCI. Aim 2: Determine the age-dependent therapeutic effects of targeting mitochondrial bioenergetics in SCI. We hypothesis that pharmacologically uncoupling mitochondrial respiration, thereby attenuating mitochondrial ROS production, will alter SCI inflammation and improve recovery in aged SCI mice