Abstract (Description) Live and intact cornea maintains an electric potential difference across the epithelium, the transepithelial potential difference (TEP). The compromised epithelial barrier in corneal wounds collapses the transepithelial potential at the wound site, resulting in naturally occurring endogenous electric fields that point towards the wound center from adjacent intact tissues. These naturally occurring wound electric fields (wEFs) provide powerful signals that stimulate and guide cells to migrate into the wound to initiate healing. We demonstrated that these electrical signals could override other directional cues, such as injury stimulation, free edge and mechanical forces, in guiding migration of corneal epithelial sheets and large groups of cells. Our long term goal is to elucidate the molecular mechanisms that generate and regulate the wound electric fields, i.e. to discover the “molecular generators”, and to use this knowledge to develop new therapeutic strategies to collectively mobilize cells (tissues) to heal chronic wounds and non-healing wounds. Our previous research has identified key ionic mechanisms and “molecular generators” that produce and regulate wEFs. Importantly, we demonstrated in three diabetic models that wEFs are defective and this correlates very well with impaired healing. Using high throughput screens, we also identified novel molecular mechanisms directing the responses of human corneal epithelial cells (CECs) to physiological electric fields. In this application, we will dissect the defective electrical signaling and impaired responses of epithelial cells in diabetic cornea. We therefore propose a comprehensive study to (1) elucidate ionic mechanisms underlying defective electrical signaling in diabetic corneal wounds, and to build a mathematical model that simulates wound electric fields; (2) determine how high glucose and oxygen uptake regulate electrogenic machinery, and how these mechanisms are impaired in diabetic cornea. Through completion of these aims, our goal is Aim (3) to electrically facilitate healing of diabetic wounds by correcting defects in generation of electrical signals.