PROJECT SUMMARY/ABSTRACT This application addresses the general hypothesis that collagen XII is essential for the acquisition of corneal stroma structure and function, and for reacquisition after injury. The concept that collagen XII modulates stromal wound healing is innovative and opens multiple translational prospects. Scar amelioration is noted during wound healing in the absence of collagen XII. Our overall goal is to provide a foundation to develop applications for matrix deposition manipulation during wound healing, and provide a rational basis for pharmaceutical and surgical therapeutic interventions aimed at promoting scarless stromal regeneration. The specific aims are to: (1) elucidate the regulatory roles of collagen XII in the acquisition of stromal structure and function; (2) determine the mechanism(s) whereby collagen XII regulates stromal wound healing; and (3) identify therapeutic interventions involving modulation of collagen XII to decrease human stromal scar formation during wound healing. The aims will test the hypotheses that: (1) differential and regulated expression of collagen XII is a critical mechanism required for acquisition of stromal structure and function; (2) collagen XII expression patterns observed in development and maturation are recapitulated during adult stromal wound healing to regulate stromal healing and scar formation; and (3) down-regulating collagen XII expression favors stromal regeneration over scarring. Therefore, modulation of collagen XII expression will have a positive impact on the reacquisition of normal stromal structure and function. This proposal will have significant impact, providing critical information for the development of novel medical and surgical therapies for patients with stromal scars, by far the most common indication for anterior lamellar and penetrating full thickness transplantation in America.