Grant: Operating Grant

More than 30 million patients in North America receive steroid drug treatment. The therapeutic indications are widespread but side effects are common and of great importance to patients. Chronic glucocorticoid therapy induces detrimental effects in several tissues including the skin where it causes skin atrophy. When encountering an accidental or surgical trauma, impaired tissue repair is one of the serious complications of glucocorticoid therapy. Glucocorticoids affect almost every phase of wound healing due to their inhibitory effects on gene expression in various cells involved in healing. Transforming growth factor-beta 1 (TGF-ß1) is a naturally-occurring molecule which regulates skin inflammation and tissue maintenance. It serves as a strong inhibitor of hair follicle stem cell growth and has been directly implicated as a significant factor in hair growth regulation. TGF-ß1 is produced as an inactive molecule and needs to be activated to function. One of the main activators of TGF-ß1 is an integrin that is expressed on the epithelial cell surface. We have recently demonstrated that this integrin is localized in hair follicle stem cells where it could keep these cells quiescent via TGF-ß1 activation. Our work has also demonstrated that mice engineered to lack this integrin (ß6-/-) have accelerated hair growth and delayed hair regression. In addition, steroid-impaired wounds heal significantly better in ß6-/- mice than in normal mice. The aim of this research proposal is to further investigate the role of this integrin in hair stem cells and healing of steroid-impaired wounds. Our hypothesis is that this integrin naturally suppresses stem cell proliferation in hair follicles. When patients receive corticosteroids, these drugs further inhibit stem cells delaying reepithelialization of wounds. Use of inhibitors of this integrin could potentially reduce stem cell suppression and provide a useful therapeutic tool to improve outcomes of steroid-impaired wound healing.