The goal of this research is to better understand the mechanism by which glucocorticosteroid hormones induce apoptosis in lymphocytes. Glucocorticoid-induced apoptosis contributes to homeostasis in the immune system. Also, because of their ability to induce apoptosis in immature lymphocytes, glucocorticoids are among the most useful agents for treatment of lymphoid malignancies. By understanding the mechanism of glucocorticoid-induced apoptosis we will be better able to decipher mechanisms by which malignant lymphocytes develop resistance to glucocorticoid therapy and be able to discover new therapeutic targets for use in treatment of lymphoid malignancies. Although calcium and alterations in redox regulation have been identified as critical components of this cell death process, there is abundant evidence that glucocorticoid receptor-mediated changes in gene transcription (i.e., induction of a """"""""death gene(s)"""""""") initiate the cell death process upstream of calcium elevation and oxygen radical formation. Using gene expression profiling we identified three glucocorticoid-induced genes that are potential """"""""death genes"""""""", txnip, tdag8 and bim. This proposal tests the hypothesis that induction of txnip and/or tdag8 initiates signaling pathways that mediate the cell death process, including calcium elevation and oxygen radical accumulation, and that the downstream induction of bim triggers the execution phase of apoptosis. The first two aims investigate the roles of txnip and tdag8 in apoptosis, linking their induction to oxygen radical accumulation and/or signaling pathways that induce bim expression.
The third aim i nvestigates the relationship between induction of these genes and calcium signaling, focusing on the role of inositol 1, 4, 5-trisphosphate receptors in this process.
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