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 ?2-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-SCI recovery period (7 DPI) and plateau phase (?15 DPI), with and without formoterol treatment in mice; 2) Elucidate the mechanisms of epigenetic modifications on the transcription of mitochondrial genes during the transition from recovery to plateau phase post-SCI, with and without formoterol treatment; 3) Assess the pharmacological efficacy of inhibiting epigenetic events on MB and recovery post-SCI in vivo, with and without formoterol treatment. Successful completion of this proposal could provide integral information into the recovery plateau observed after SCI. I am using an FDA-approved compound, male and female mice and initiating treatment up to 8h after injury, emphasizing the clinical applicability. This proposal will also directly assess the therapeutic potential of my findings by determining if modulation of epigenetic status improves recovery after injury. My mentoring team has formulated a comprehensive career development plan that includes exposure to a rich educational environment, opportunities to improve oral and written communication skills and mentoring on project and laboratory maintenance to ease transition to independence. This project and training will facilitate the completion of my long-term career goal of becoming and independent VA researcher.

Public Health Relevance

Spinal cord injury (SCI) is a debilitating condition without meaningful treatment. The Department of Veterans Affairs provides care and disability compensation for over 42,000 veterans suffering from SCI, with the annual healthcare cost for SCI victims being 6.5 times greater than that of the average veteran. Treatment of SCI involves intensive care immediately following injury, as well as rehabilitation and treatment for any resulting complications. Unfortunately, recovery post-SCI often plateaus after about 12 months. The reason behind the development of this plateau phase is not fully understood. If the plateau phase could be prevented or reversed, perhaps continual recovery following injury could be possible. The proposed studies will attempt to address this gap in knowledge, which could prove beneficial for not only the patients themselves, but also for the healthcare system in general.

National Institute of Health (NIH)
Veterans Affairs (VA)
Veterans Administration (IK2)
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Special Emphasis Panel (ZRD1)
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Southern Arizona VA Health Care System
United States
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