MECHANISM OF ACTION OF STEROID HORMONES

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The long-term objectives are to understand the molecular and metabolic events involved in the initiation and implementation of each of the biological effects of adrenal glucocorticoid hormones. We have made progress towards this goal by the discovery of a few (6-11) very rapid inductions of proteins and mRNAs that appear to initiate the hormone effects in each of the normal target tissues; thymus, fat, liver and fibroblastic cells. One of these, glucocortin, is of special interest as the most rapid induction in all target cells. Another, protein 1N may be the physiological inhibitor of glucose transport and/or a member of the lipocortin family. Portions of our continuing investigations are aimed providing more detailed information about these mediators in the different target cells. Studies on induction mechanisms will sort out primary and secondary responses and gather further information about subcellular locations, DNA binding, and structural relationships with other molecules. We will investigate the specificity of individual inductions for a variety of glucocorticoids with aim of possible sub-classifications. We will further investigate functions by observing the actions of the mediators themselves and antibodies to them in subcellar systems. Other work is aimed at the development of oligonucleotide and antibody probes. Then, starting with glucocortin we will undertake molecular cloning. In addition to the structural information gained about these proteins and their genes this will allow the eventual use of expression vectors for the further exploration of their functions in cultured cells. Clinical relevance. The therapeutic benefits that immunosuppressive and anti-inflammatory effects of glucocorticoids offer in chronic disease states, organ transplantation, and cancer chemotherapy are offset by the life- threatening side effects of bone resorption and connective tissue wasting. It seems likely that mediators of the individual glucocorticoid actions themselves or related therapeutic agents derived by genetic engineering will eventually be available to the clinician for the production of desirable actions of glucocorticoids without these unfortunate side effects. These studies will also provide fundamental information about bioregulatory mechanisms in thymus cells; so the fundamental information may eventually have relevance to research on AIDS.