Project Summary/Abstract The cornea is the optically clear, curved tissue that provides the majority of refractive power in the eye. Improper healing of corneal wounds is a serious issue that can lead to blindness or permanent refractive visual complications. We have demonstrated that the cornea becomes intrinsically photoreceptive after injury, and it is able to entrain its circadian clock to light cycles in vitro. We have observed that the rate healing of wounded mouse corneas is accelerated by violet light both in vivo and ex vivo. We have identified a class of highly motile Opn5-expressing epithelial cells induced in the cornea after wounding. Opn5 is an opsin protein which is sensitive to short wavelength light. Mice which lack Opn5 show aberrant responses to corneal wounding, such as impaired re-epithelialization and stromal abnormalities. The central hypothesis of this proposal is that light modulates corneal wound healing via an Opn5-dependent mechanism. We have also found evidence of non-photic effects mediated by Opn5. The specific aims of this project include the following: (Aim 1) testing the light regimen necessary for photic healing acceleration in murine corneas, (Aim 2) characterizing the mechanism of signal transduction within Opn5-expressing cells, and (Aim 3) testing the hypothesis that diffusible factors function in the induction of Opn5 expression and its communication with the rest of the cornea. Our approach will be to utilize both in vivo and ex vivo experimentation with a number of mouse models in which the Opn5 cells can be visualized or have their molecular constituents isolated from whole corneal cell lysate. We will also use cultured cell lines to uncover the factor or factors necessary to induce Opn5. The innovation of this project lies in applying recently discovered extra-retinal photoreception to analyses of wound healing and the health of the corneal surface. Another aspect of this innovation will be to extend the results of mouse studies to corneal cells from human and non-human primates to analyze the translational potential of the observations made in mouse models. The potential impact of this work will be to harness the role light plays in corneal wound healing through opsin agonists/ antagonists to facilitate wound closure and the avoidance of scarring.