The goal of this project is to determine the role of epigenetic modifications of mitochondrial genes in the induction of the plateau phase after spinal cord injury (SCI), and to exploit these modifications to promote recovery. SCI is a devastating disorder often resulting in loss of function below the injury site. In recent years, service members have been threatened by more advanced warfare, such as improvised explosive devices, ultimately inducing more severe and complex injuries, including SCI. The devastating and debilitating nature of these injuries has not been lessened. The Department of Veterans Affairs (VA) is the largest healthcare network for individuals suffering from SCI, providing care for 25% of total victims in the United States. Improved therapeutics for the treatment of SCI would greatly benefit not only sufferers, but also the VA healthcare system. SCI is defined by direct trauma to the spinal cord, which disrupts the vasculature, leading to decreased oxygen delivery within the area and reducing the ability of mitochondria to maintain cellular energetics. Thus far, the majority of studies targeting mitochondrial dysfunction following SCI have focused on downstream aspects of mitochondrial function (e.g. antioxidant defenses). Reestablishment of mitochondrial function through pharmacological induction of mitochondrial biogenesis (MB) remains an underexplored but novel strategy. I previously reported that treatment with the mitochondrially biogenic FDA-approved β2-adrenergic receptor agonist formoterol beginning up to 8h after SCI improves spinal cord mitochondrial function, decreases lesion volume and enhances locomotor recovery by 7 days post-injury (DPI). Consistent with other published data, the majority of the improvements observed with formoterol occurred within the first 2 weeks, after which recovery plateaued. A similar effect is observed in humans, with the majority of recovery taking place within the first year then reaching a plateau. The mechanism behind the development of this plateau phase, however, is not fully understood. By determining the mechanism of its formation, the plateau phase could be prevented and/or reversed, potentially allowing for continued recovery following injury. My preliminary studies revealed genetic differences within the injured spinal cord of formoterol-treated mice between the recovery phase (7 DPI) and the plateau phase (15 DPI), namely a decrease in genes associated with mitochondrial function, and a concurrent increase in genes associated with epigenetic modifications. Therefore, I hypothesize that epigenetic alterations contribute to decreased transcription of mitochondrial genes within the spinal cord during the plateau phase, preventing continued recovery of mitochondrial function and limiting the efficacy of formoterol treatment in mice. To address this hypothesis, I propose the following Specific Aims: 1) Further elucidate the genetic profile within the spinal cord during the post-...