MECHANISMS FOR CHRONIC UVR-INDUCED DAMAGE TO SKIN

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DESCRIPTION: (Adapted from the applicant's abstract) - The long-term objective of this research is to elucidate mechanisms responsible for the dermal remodeling that occurs in response to exposure of skin to solar UV radiation (UVR) over many years with the hope of devising strategies to inhibit these tissue alterations. Age-related changes in skin (photoaging and intrinsic aging) result in clinically important physiological changes and are a significant medical problem in the elderly. The approach taken in this proposal is to investigate the importance of mediators produced by three cell types, keratinocytes, mast cells, and neutrophils in the development of photoaged skin and particularly, in the increased synthesis of tropoelastin and glycosaminoglycans (GAGs). The first specific aim is to determine whether chronic exposure of skin to UVR induces production of mediators from epidermal cells that initiate dermal photoaging. This will be accomplished by: a) Determining whether the epidermis is the primary site for absorption of UVR that initiates changes in elastin, GAGs, histology and tropoelastin mRNA steady-state levels. b) Assessing the ability of supernatants from keratinocytes that are exposed to UVR in vitro to stimulate fibroblast synthesis of tropoelastin and GAGs and increase tropoelastin steady state mRNA levels. Possible UVR-induced mediators will be evaluated. The second specific aim is to determine whether mast cell products are important mediators in the mechanism for dermal photoaging. This will be accomplished by: a) Comparing the elastin, GAGs, and histology produced by chronic UVR exposure of mast cell-deficient mice and normal mice. b) Determining whether dermal fibroblasts increase their synthetic activity in response to mast cell products in vitro using mixtures from activated and degranulated mast cells and selected mast cell products. Rates of synthesis of tropoelasin and GAGs, and mRNA levels for tropoelastin will be measured. The third specific aim is to test the hypothesis that products of neutrophils are important mediators in the mechanism for dermal photoaging. Neutrophil elastase-deficient mice will be employed, and synthesis of GAGs, character of GAGs and histology will be used to measure the effects of chronic UV by exposure. Neutrophil products will be tested in vitro for their ability to alter fibroblast synthetic activity.