The importance of vitamin A derivatives (retinoids) in the maintenance of normal epithelial growth and differentiation has been known for 6 decades, but the mechanisms, the sites of action, and the physiologically active retinoids involved remain obscure, despite the now widespread use of retinoids in medicine for the treatment of skin diseases such as acne and psoriasis. Among their less understood properties is their potent ability to induce hyperplasia of the epidermis, the target organ for many of their therapeutic uses.
The aim of this proposal is to investigate the mechanisms of the induction of epidermal hyperplasia by retinoids, and to ultimately establish if the induced hyperplasia has a primary or secondary role in the action of the retinoids in vivo. The studies are designed to reveal if retinoids are acting on specific cells or select cell populations in the epidermis, and to pinpoint the critical metabolic factors involved. Studies will be carried out initially using the naturally occurring derivatives all-trans-retinoic acid (RA), retinol, and the more potent synthetic retinoid arotinoid ethyl ester.
The specific aims of the proposal will be achieved through the insight and answers generated in the following studies. Retinoids will be applied to dorsal skin of hairless mice and their effects on the incorporation of radioactively labeled precursors into proteins and nucleic acids of the epidermis observed using autoradiography and by extraction of the RNA, proteins, and glycoproteins. This will provide information on the specific structures of the epidermis involved in retinoid action and extend our understanding of the biochemical changes which led to hyperplasia. A more specific characterization of the macromolecules involved will be achieved by studying their behviour using electrophoresis and high performance liquid chromatography. The ability to induce hyperplasia will be correlated with the effect of different retinoids at varied doses on biochemical events, particularly the activity of ornithine decarboxylase, which they are known to affect. The metabolism of retinoids in the epidermis will be studied during the early crucial stages of the induction of hyperplasia to determine if this is required for the induction process, and to identify common metabolic routes which could indicate the mechanisms involved.
| Connor, M J; Smit, M H (1987) The formation of all-trans-retinoic acid from all-trans-retinol in hairless mouse skin. Biochem Pharmacol 36:919-24 |
| Young, A R; Connor, M J; Lowe, N J (1986) U.v. wavelength dependence for the induction of ornithine decarboxylase activity in hairless mouse epidermis. Carcinogenesis 7:601-4 |
| Connor, M J; Ashton, R E; Lowe, N J (1986) A comparative study of the induction of epidermal hyperplasia by natural and synthetic retinoids. J Pharmacol Exp Ther 237:31-5 |
