IMPACT OF AGING, ISCHEMIA AND CYTOKINES ON WOUND HEALING

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DESCRIPTION (adapted from applicant's abstract): Chronic non-healing wounds are a major health problem commonly found in the elderly population. Local tissue hypoxia, resulting from underlying health problems such as diabetes, venous stasis and peripheral vascular disease, is a common feature accompanying all types of chronic wounds in the clinical setting. The investigator's long-term goal is to develop methods for the prevention and treatment of chronic wounds in the elderly based on an understanding of pathobiological mechanisms of chronic wounds and the function of growth factors in coordinating wound healing in the chronic wound microenvironment. Preliminary studies have focused on developing an ischemic murine model to generate a hypoxic tissue environment for wound healing studies. Using this model and cell culture, the investigators have characterized ischemic modulation of TGF-b and matrix metalloproteinase expression in young animals and cells. Their overall hypothesis is that tissue hypoxia negatively impacts wound healing in aged systems, with specific impairment of the pro-healing effects of the growth factor TGF-b1. They further hypothesize this impairment occurs at the level of TGF-b1 expression and signal transduction that, in part, limits healing by affecting TGF-b1 control of type I collagen expression and matrix metalloproteinase (MMP) expression/ activity. Control of type I collagen expression and MMP activity is required for a normal healing process. This hypothesis will be tested using the ischemic flap wound in an aged murine model. This proposal presents experiments designed to elucidate the cellular and molecular mechanisms altered in aged systems that affect the normal role of TGF-b1 in wound healing. Their specific aims are to (1) characterize the effect of ischemia on the wound healing of aged mouse wounds, and examine hypoxia-modulated alterations of TGF-b isoforms and TGF-b receptors in wound tissue and fluid; (2) examine expression of downstream effector genes of TGF-b1, specifically collagen and collagen-degrading matrix metalloproteinases (MMPs), in aged mouse ischemic wounds; (3) investigate the molecular and cellular basis for hypoxia-impaired wound healing in aged mice by extending in vivo observations to primary cultures of aged murine dermal fibroblasts to examine hypoxic modulation of early TGF-b signal transduction; (4) to investigate the hypoxia modulation of collagen and matrix metalloproteinase expression in aged murine dermal fibroblasts and the potential role of TGF-b1 in mediating these changes.