DNA Repair Mechanisms Protect Against the Pathological and Functional Consequences of Spinal Cord Injury and Associated Neuroinflammation (R-11277)

Spinal cord injury (SCI) is a devastating neurological disorder of the central nervous system. While the primary traumatic event determines the overall severity of the SCI, the secondary neuroinflammation, associated with formation of reactive oxygen species (ROS), expands the damage, and exacerbates all deficits. ROS can react with DNA and cause damage to the genetic material, leading to cell death, senescence, or transformation. To avert these adverse outcomes, cells have evolved DNA repair mechanisms. As ROS formation is a given following SCI, it is likely that associated oxidative DNA modification is a critical factor in the extensive pathological damage observed following SCI. Therefore, I hypothesize that efficient DNA repair will be required to avoid the severe pathological outcomes and functional consequences of SCI and its consequent chronic neuroinflammation. First, I will assess DNA damage markers and DNA repair gene expression in SCI mice. Then, I will examine the role of some critical DNA repair genes using relevant cell culture models. Next, I will elucidate the effects of targeted DNA repair deficiency in SCI using genetically-defined mouse models. Finally, I will evaluate several DNA repair-related therapeutic paradigms to improve recovery following SCI. This new view on SCI pathology will result in novel insights into the molecular processes that affect injury severity and provide critical information towards the design of effective therapeutics.

Keywords:immunology, spinal cord injury

Disciplines:Biogerontology, Applied immunology, Inflammation, Innate immunity, Immunomodulation therapy