EXCEEDTHE SPACEPROVIDED. Ultraviolet radiation (UVR) has multiple deleterious and beneficial effects on human skin. Single exposures of normal skin to solar UVR elicit inflammation,melanogenesis, vitamin D production, and may cause immune suppression. Chronic exposure to solar UVR produces non-melanoma skin cancer, influences development of melanoma and leads to skin photoaging. UVR is also used to treat skin diseases, most notably psoriasis. Recent work has demonstrated that cell responses to UVR such as survival responses and apoptosis involve early signaling events in and near the plasma membrane. These responses are observed after long wavelength UVA radiation as well as shorter wavelength UVB radiation, which had previously been thought to target nuclear DNA exclusively. The long-range objectives of this research are to understand the molecular mechanisms for solar UVR-induced alterations in skin in order to prevent adverse effects and to develop UVR- based therapies for skin diseases. The proposed research is designed to provide fundamental understanding of the the primary photochemistry, with emphasis on the events occurring at the plasma membrane, on UVR induced new gene expression, apoptosis and generation of inflammatory mediators in skin cells. Studies in human keratinocytes and fibroblasts will be carried out to accomplish these specific arms: 1)To test the hypothesis that UVR photochemistry at the plasma membrane can initiate early signaling events in the plasma membrane that may mediate gene expression and apoptosis. Endogenous chromophores in and near the plasma membrane will be selectively excited using evanescent wave radiation; reactive oxidizing species (ROS), clustering of membrane receptors, induction of gene expression and apoptosis will be assessed. 2) To evaluate the ability of specific ROS to initiate signaling events leading to induction of gene expression and apoptosis when created either at the plasma membrane or specific subcellular locations. 3) To test the hypothesis that the plasma membrane content of 7-dehydrocholesterol (7-DHC) alters UVA-induced production of inflammatory mediators. Human keratinocytes and fibroblasts will be supplemented with 7-DHC, and UVA-induced production of PGE2 and IL-lcc will measured.
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