The long term objective of this work is to increase our understanding of the mechanisms that regulate gene expression in epidermis, and the changes in the mechanisms that occur in diseases. This increased understanding will lead to specific and effective treatments of such hyperproliferative and inflammatory processes as wound healing and psoriasis. The molecular signals in keratinocytes commonly activate multiple parallel intracellular pathways. Defining the pivotal signal transducing proteins, as well as the proteins that transduce the specific parallel effects will greatly increase our understanding of the regulatory processes in epidermis. The approach has four basic steps: to identify the molecular signals that operate in keratinocytes, to define the relevant signal transduction mechanisms, to characterize the patterns of transcription factor activation and to develop specific modifications of these processes using latest discoveries of molecular biology. Having already completed the first step, we focus in this proposal on the last three steps. Using DNA transfection and specific antibodies, the signal transduction mechanisms will be defined for two families of growth factors/cytokines, the EGF/TGFalpha and the TNFalpha/IL-1 family. Both are extremely important in cutaneous inflammatory processes. The patterns of transcription factor activation will be characterized for AP1, NFkappaB and C/EBPbeta proteins. These regulate gene expression in healthy and diseased epidermis. Finally, the proteins involved in signaling and regulation of gene expression will be inhibited using specific drugs, antisense oligonucleotides and target DNA binding sites in order to understand their roles in epidermal biology and pathology, and to develop specific therapeutic approaches.
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