Abstract Corneal nerves are important for cornea health, and for protecting the eye from outside elements. They are mostly nociceptive, coding discomfort and pain in response to mechanical stimulation, temperature and/or chemical stimulation. Disease, infection and ocular surgery all damage corneal nerves, with long-term consequences in terms of pain, dry eye, recurrent erosions, opacity and even blindness. Yet, there are no effective clinical therapies for nerve dysfunction once fibrosis has occurred. Our prior work allowed us to better understand factors that control myofibroblast differentiation in the large wounds generated in human and cat corneas. This work also led to the observation of a nefarious interaction between wound myofibroblasts and regenerating corneal nerves. Pre-treating the wound area with anti-fibrotic agents can mitigate this problem, but in most cases of accidental injury or infection, patients present after myofibroblast differentiation/fibrosis have occurred. The issue then is no longer preventing fibrosis, but rather overcoming the contact inhibition between nerves and persistent myofibroblasts. We recently found that the PPARg ligand Troglitazone stimulates neurite outgrowth and causes myofibroblasts de-differentiation in vitro and in vivo. Importantly, these effects can be mimicked in vitro by a compound that spares PPARg and targets the mitochondrial pyruvate carrier (MPC). Together with recent literature, our pilot data form a strong premise for critically testing the hypothesis that inhibiting the MPC may facilitate metabolic remodeling in both regenerating nerves and activated myofibroblasts to overcome the blocked reinnervation inherent in later stages of post-injury corneal fibrosis. To test this hypothesis, we will: Aim 1, identify metabolic changes through which inhibiting mitochondrial pyruvate transport promotes neurite outgrowth of peripheral sensory neurons in a simulated wound environment; Aim 2, assess if similar or different mechanisms (as in Aim 1) underlie de-differentiation of corneal myofibroblasts; and Aim 3, contrast the relative efficacy of different mitochondrial modulators for overcoming myofibroblasts’ inhibition on corneal nerve regeneration in vivo. Fundamentally, the proposed research will ascertain if MPC activity is key to overcoming fibrosis and/or its associated inhibition of neurite outgrowth. We will confirm target specificity through genome manipulation in both corneal fibroblasts and peripheral sensory neurons, determine how targeting impacts mitochondrial function, and identify signals downstream of metabolic rewiring that are necessary to mediate these effects. Since the MPC has never been studied in the context of peripheral wounding, our results could unveil new, broadly-relevant aspects of its function. Ultimately, the proposed research aims to unravel novel molecular mechanisms that may play a substantial, hitherto unexplored role in large, established, fibrotic wounds. Defini...