GLUCOCORTICOIDS AND LYMPHOCYTE CATABOLISM

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The longterm goals of this research are to achieve an understanding of the mechanisms by which adrenal steroid hormones regulate lymphocyte survival and thereby alter immunological function. We propose to further study the mechanism of glucocorticold action in rat thymic lymphocytes under well controlled in vitro conditions. Previous work from our laboratory indicates that glucocorticoids affect not only macromolecular synthetic processes, but also more strikingly, the degradation of protein, RNA and DNA. We hypothesize that glucocorticoid induced selective DNA degradation (perhaps via gene deletion), leads to inappropriate RNA metabolism, subsequent aberrant protein metabolism and thus eliminates a cell's capacity to cope with its environment. To test this hypothesis, we propose to: 1) quantify and define further, glucocorticoid induced protein degradation in sensitive and resistant lymphocytes; 2) quantify and define the specificity of glucocorticoid induced RNA degradation in sensitive and resistant lymphocytes by assessing RNA turnover and in vitro translation products; 3) study the effects of glucocorticoids on DNA degradation in sensitive and resistant lymphocytes; 4) finally we will study the selectivity of glucocorticoid induced DNA degradation. Are active genes preferentially digested over silent counterparts? We will determine the extent to which each of these processes occur following non glucocorticoid induced cell death so as to firmly prove or disprove the hypothesized cause/effect relationships. These studies will provide insight into the mechanisms by which adrenal steroids regulate lymphocyte function, provide further details on the mechanisms of cell death and test the notion that "gene deletion or degradation" is a hormonally regulated process in mammalian cells.