Molecular generators at corneal wounds produce and regulate the wound electrical signals

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DESCRIPTION (provided by applicant): Our goal is to electrically heal wounds. Experiments from our own lab and others have demonstrated that electric fields occur naturally at corneal wounds and provide a powerful signal to guide migration of corneal epithelial cells. We demonstrated that the 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. It is however not known how cornea wounds generate the electric "signal". We propose to discover molecular "generators" at corneal wounds. Uncovering these generator molecules will give us molecular targets which we can stimulate to produce stronger electrical signals, and thus facilitate healing. In this proposal, we will 1) characterize calcium-activated chloride channels (CaCCs) in corneal epithelial cells using electrophysiology and genetic models; 2) determine responses of CaCCs to injury and their roles in generating wound electric currents; and, 3) correct the defective wound electric signals (and wound healing) in diabetic rats and ANO1 knockout mice. We expect that the novel mechanisms discovered will provide fundamental insights as well as practical strategies for healing of chronic corneal wounds.