PATHOPHYSIOLOGY & CHEMOTHERAPY IN PSORIASIS AND CANCER

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This proposal is a continuing study of cutaneous disease, manifest in part by abnormalities in cell proliferation. The goals are to obtain knowledge on the pathophysiology of psoriasis, ichthyosiform dermatoses, and other hyperproliferative skin diseases, that can be used to develop pharmacologic approaches for their clinical improvement or cure. Controls of epidermal proliferation and the influence of extracutaneous factors on these controls will be studied in normal, uninvolved, and psoriatic epidermis for clues to the etiopathogenesis of psoriasis. The biological and biochemical factors known to influence epidermal cell proliferation and differentiation, e.g., psoriatic stimulants, physiologic growth factors, and tumor promoters, will be examined in several experimental models that utilize the genetically predisposed uninvolved skin of psoriasis. A new keratinocyte model employing somatic cell fusion techniques will be used to study hyperproliferative epidermal diseases with genetic components. Fusions betwen HeLa and keratinocytes to produce immortal cell lines containing the genetic makeup of psoriasis or other genetic epidermal diseases will provide a valuable new tool for basic and therapeutic studies. By innoculating the keratinocyte hybrids into nude mice, functional expression of proliferation and differentiation abnormalities in vivo can be studied. The second new model, cyclosporine-immunesuppressed rats, which permit the long-term growth of human skin, will greatly facilitate pathophysiologic investigations of normal and diseased skin in vivo. The basic cellular mechanisms by which the folic acid antagonists and inhibitors of polyamine biosynthesis selectively influence epidermal hyperproliferation in the psoriatic process will be studied to develop pharmacological approaches for safer and more effective forms of therapy.