Our long-term goal is to define the mechanisms responsible for delayed wound healing in aging in hopes of developing novel therapies. Hyperbaric oxygen has long been utilized in treating the difficult to heal wounds and has shown promising results on healing wounds from aging individuals. However, very little is understood about the molecular mechanisms involved. We plan to study the mechanisms involved in HBO's increase in wound healing rates by focusing specifically on the expression and function of the platelet derived growth factor receptor-beta (PDGRB) in fibroblasts. Our laboratory has shown that PDGFRB expression is reduced in fibroblasts derived from older donors. Reduced proliferation correlates to a reduction in functional PDGFRB expressed. Hyperbaric oxygen treatment corrects the age associated defect by increasing both PDGFRB number and proliferation of fibroblasts. Our preliminary studies suggest that HBO upregulates PDGFRB expression through a nitric oxide (NO)-dependent mechanism. NO production is required for proper wound healing and insufficient NO production has been linked to delayed wound healing in both animal and human studies. Our hypothesis is that the age associated dysfunction in PDGFRB expression and function may be corrected by HBO in an NO-dependent manner. We plan to define the oxygen-responsive element(s) (ORE) within the PDGFRB promoter and determine whether these elements function differently in human fibroblasts derived from old, young, and newborn donors. We will focus on our in vitro model system and delineate the role of the fibroblast specifically. Findings from these studies will have important implications for novel therapeutic approaches in aging. ? ? ?
