In many common and serious dermatological diseases involving the epidermis (psoriasis, ichthyotic conditions, skin cancers, and inflammatory skin diseases) increased and abnormal epidermal proliferation is associated with impaired and delayed epidermal differentiation. These different aspects of the diseases may be casually linked by specific products of the proliferating epidermis inhibiting and interferring with specific post-translational modification of several epidermal proteins. The modifications to be studied are the formation of Epsilon-Gamma-glutamyllysine cross-links in epidermal keratins and cell envelope proteins catalyzed by epidermal transglutaminases and the disulfide bond formation in epidermal keratins catalyzed by epidermal sulfhydryl oxidases. Epidermal polyamines, cysteine and cysteine containing peptides would be critical intermediates in these reactions. The studies will be biochemical and immunological and involve human epidermal tissue culture, studies of rat epidermis from the fetal, newborn and adult periods and human skin biopsies. The detailed pathway of polyamine and precursor in epidermis will be delimited with biosynthetic radioisotope studies and determining radioactive peptides by degradative techniques, and identification of products with high performance chromatographic techniques. The role of polyamine continuing proteins and peptide as """"""""anti-zymes"""""""" for epidermal ODC will be tested, as will the role of epidermal proteins and their peptides as negative feedback inhibitors of protein synthesis. The ability of sulfhydryl oxidase to cross-link epidermal keratins and the effects of this on interactions of keratin with stratum corneum basic protein and the effect of polyamines on this interaction will be studied as well. Both transglutaminase and sulfhydryl oxidase are amenable to pharmacological control with inhibitors and activators, several of which can be applied topically, such drugs may allow one to alter and correct the defects in the epidermis in disease. As many of these diseases have no long-term safe and rationally derived therapy there is a direct therapeutic effect expected from these studies.
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