Regulation of Skin Wound Epithelialization by Galectin-3

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DESCRIPTION (provided by applicant): Galectins are a family of animal lectins defined by their affinity for ¿-galactosides and consensus protein sequences. Galectin-3 is the most extensively studied member and is expressed by a variety of cells, including keratinocytes and macrophages. Our current view is that endogenous galectin-3 can regulate cellular functions, such as cell migration, growth and apoptosis, through intracellular mechanisms. In the mean time, when added exogenously to cultured cells, galectin-3 can induce transmembrane signal transduction by binding to cell surface glycans. Existing information as well as our preliminary studies suggests that galectin-3 may contribute significantly to the wound healing process through its effects on macrophages and keratinocytes: 1. Studies of various inflammation models using gal3-/- mice have provided convincing evidence for the role of galectin-3 in promotion of inflammation. In addition, we have recently demonstrated that endogenous galectin-3 positively regulates migration of macrophages. Thus, we propose that endogenous galectin-3 can promote migration of monocytes/macrophages during wound healing. We also propose galectin-3 added to skin wound sites can attract monocytes/macrophages. 2. We have found that endogenous galectin-3 positively regulates migration of keratinocytes and galectin-3 is present at the leading edges of migrating keratinocytes. We have also demonstrated that galectin-3 plays an important role in skin wound re-epithelialization in mice both ex vivo and in vivo. Our collaborators have shown that endogenous galectin-3 is essential for re-epithelialization of corneal wounds and recombinant galectin-3 promotes corneal wound repair. The proposed studies are designed to definitively establish the role of galectin-3 in the inflammatory and re-epithelialization phases of skin wound repair. We will address the functions of both galectin-3 present endogenously and exogenously added recombinant protein. 1: Investigation of the role of galectin-3 in the function of macrophages during skin wound healing 2: Investigation of the mechanism by which galectin-3 regulates keratinocyte migration 3: Investigation of the effects of exogenous galectin-3 on wound re-epithelialization The completion of the proposed studies should afford a comprehensive picture of how endogenous galectin-3 functions in the inflammatory and re-epithelialization phases of skin wound healing. The studies should also reveal the effects of exogenously added galectin-3 protein to skin wound re-epithelialization. The information obtained will help set the stage for investigation of recombinant galectin-3 as a therapeutic agent for treatment of skin wounds. PERFORMANCE SITE(S) (organization, city, state) UC Davis, Medical Center Sacramento, CA Skin wounds that do not heal are a major medical problem. This research project deals with understanding of the functions of a protein called galectin-3 in terms of its regulation of properties of different cell populations involved in healing of skin wounds. The long-term goal is to develop improved methods for treatment of skin wounds.