As individuals age, they are more likely to develop certain age-related pathologies such as: metastatic tumors, vascular dysplasia, and impaired wound healing. It has recently been shown that a gene, that is expressed at high levels in young fibroblasts and is dramatically reduced in senescent cells, exhibit potent anti-migratory activity toward vascular endothelial cells. This protein, called EPC-1, is produced by fibroblasts and detected in elevated levels in the dermis of the skin. It acts on dermal endothelial cells and potentially other cells such as keratinocytes and melanocytes in the epidermis. We hypothesize that there are fibroblast cells in the dermis that have lost the ability to produce EPC-1 in a mosaic fashion and this loss of EPC-1 plays a role in disturbing the balance of proteinases and their inhibitors. In turn it is this decline in expression and/or response that plays a role in the development of metastatic tumors and vascular dysplasias. In this Pilot Project (PA-00-053), it is our objective to evaluate EPC-1 expression in the skin in situ, to develop a cellular model that will guide us in future experiments, and to determine how EPC-1 blocks cell migration by interfering with the proteolytic actions of matrix metalloproteinases on the extracellular matrix. Understanding how EPC-1 interacts with the extracellular matrix to control proteolysis and its loss in aging has potentially profound implications for our understanding of neoplasia, metastasis, normal wound healing, and a host of chronic skin diseases that afflict the elderly.
| Francis, Mary Kay; Appel, Stacia; Meyer, Christine et al. (2004) Loss of EPC-1/PEDF expression during skin aging in vivo. J Invest Dermatol 122:1096-105 |
