VA treats more than 26,000 people with spinal cord injury (SCI) and disorders each year, making the department the largest health care system in the world providing spinal cord care. A better understanding of axonal repair after central nervous system (CNS) injury is critical to the development of restorative treatment for people with SCI, especially the chronically injured. The overarching goal of this proposal is to understand how axonal sprouting, a form of endogenous repair mechanism in the CNS, can be enhanced and harnessed to promote functional recovery in chronic SCI. An important premise of the proposed study is that axonal sprouting from uninjured neurons represents an important and readily accessible form of axonal repair that will likely generate near-term translational value as compared to the more challenging regeneration-promoting strategies. Previous studies of axonal sprouting have focused on acute or subacute phases of SCI. The current grant mechanism will encourage us to delve into the important biology of axonal sprouting with chronic injury. This proposal builds upon our very recent published study on the impact of age on CNS axon regeneration and our unpublished preliminary data on the effect of age and chronic injury in axonal repair. Using the mouse corticospinal tract (CST) as the model system, we will test the hypothesis that sprouting can occur and contribute to functional recovery in chronic SCI, and that this endogenous repair mechanism can be enhanced through molecular intervention in the chronically injured CNS. We will use unilateral pyramidotomy injury model that severs one side of the CST to study sprouting across the midline to the denervated side. We will assess the level of CST axon sprouting in chronically injured mice, and identify effective molecular manipulations that promote such sprouting in chronically injured mice. We will also combine sprouting-promoting strategies and rehabilitative training to enhance functional recovery after a chronic spinal cord injury. Together, the proposed studies will address the potential of axon sprouting as a potentially more accessible repair mechanism to promote recovery of function in chronic SCI.