PROJECT SUMMARY Severe morbidity and mortality are commonly associated with spinal cord injury (SCI). Human patients who survive SCI frequently live with paralysis and extremely reduced quality of life and productivity. SCI often results in a permanent loss of neurons and the disruption of neural circuits that are critical for normal motor, sensory, and autonomic function. It is crucial to replenish the lost neurons and reconstruct the broken neural circuits for functional recovery. Unlike some other tissues or organs in the body, such as skin and liver, which can undergo self-repair through proliferation of endogenous stem or somatic cells, adult spinal cord exhibits minimal regenerative capacity. Cellular transplantation of stem cell-derived neural progenitors or differentiated neurons holds clinical potential 12-18. However, cell therapy is relatively inefficient due to the failure of these cells to survive or fully adopt a functional phenotype especially under the chronic phase of neural injury. In contrast to transplantation-based therapy, we propose to employ a novel strategy to reprogram endogenous reactive glial cells to mature neurons for functional recovery after SCI. Glial cells are abundant and ubiquitously distributed in the adult spinal cord. They become reactive, proliferate, and form glial scars in response to damage, and play critical roles in modulating tissue damage and repair after injury. Of note, scar formation and secretion of chondroitin sulfate proteoglycans (CSPG) by reactive glial cells (e.g. astrocytes) are inhibitory for functional improvement. Attenuating reactive gliosis or reducing CSPG activity improves posttraumatic regeneration, whereas increasing reactive gliosis worsens brain injuries. Here we hypothesize that reprogramming reactive glial cells to neurons at the injury site will reduce local glial scar formation and enhance establishment of new neural circuit resulting in functional recovery. Using a cervical C5 dorsal hemisection model (C5 DH) and forelimb functional recovery assessments in adult mice, we will test this hypothesis with three specific aims. In Aim 1, we will determine functional integration of glia-converted neurons after the C5 DH. In Aim 2, we will determine the anatomical integration of glia-converted neurons into local neural circuitry after the C5 DH. Lastly, in Aim 3, we will determine functional roles of descending supraspinal and/or propriospinal pathways over induced neurons in promoting forelimb functional recovery after the C5 DH. The proposed strategy is expected to provide alternative neuronal subtypes that may facilitate functional recovery after SCI.