Thomas J. Schmidt, Ph.D.

Professor

Assistant Dean: Office of Student Affairs and Curriculum

Cornell University, 1976

Research Interests

The major interests of my laboratory focus on understanding the mode of action of mineralocorticoid and glucocorticoid hormones. Collectively, these two major classes of adrenocorticosteroids affect the growth, differentiation and function of a wide variety of tissues and target cells. Most of the physiological responses to these hormones are mediated via their binding to intracellular receptor proteins with high affinity and specificity. Once activated by the appropriate hormone, these glucocorticoid and mineralocorticoid receptors (GR and MR, respectively) function as ligand-activated transcription factors. We are interested in how the GR and MR are autoregulated by their cognate ligands. We have shown that GR are down-regulated by glucocorticoids via an agonist-mediated decrease in GR gene transcription as well as by an agonist-induced destabilization of GR mRNA. Both of these classes of adrenocorticosteroids appear capable of modulating target tissue sensitivity by modulating the expression of their own receptors. In separate experiments, the effects of immunosuppressive drugs including FK506, rapamycin and cyclosporin A as well as ion channel blockers, such as verapamil, and quinidine, on the GR pathway have been investigated. We have demonstrated that these drugs specifically potentiate the ability of certain synthetic glucocorticoids to enhance the rate of transcription of a stably transfected glucocorticoid responsive promoter-reporter gene construct in LMCAT cells (fibroblast cell line). This response appears to reflect the fact that all of these drugs are capable of inhibiting the activity of the plasma membrane-associated multi-drug-resistant (MDR) pump, which is an ATP-dependent pump that is capable of pumping many drugs, including some steroids, out of cells. A human leukemic cell line which overexpresses this MDR pump and is hence resistant to the chemotherapeutic drug vinblastine is currently being utilized to determine how naturally occurring as well as synthetic steroid hormones themselves can inhibit this efflux pump and hence reverse vinblastine sensitivity.

Representative References

1. Medh, R.D. and Schmidt, T.J. Trans-retinoic acid and glucocorticoids synergistically induce transcription from the mouse mammary tumor virus promoter in human embryonic kidney cells. J. Steroid Biochem. Mol. Biol. 62: 129-142, 1997.

2. Medh, R.D., Lay, R.H. and Schmidt, T.J. Agonist-specific modulation of glucocorticoid-mediated transcription by immunosuppressants. Molecular and Cellular Endocrinology, 138: 11-23, 1998.

3. Mick, V.E., Itani, O.A., Loftus, R. W., Husted, R.F., Schmidt, T.J. and Thomas, C.P. The alpha-subunit of the epithelial sodium channel is an aldosterone-induced transcript in mammalian collecting ducts, and this transcriptional response is mediated via distinct cis-elements in the 5’-flanking region of the gene. Molecular Endocrinology 15: 575-588, 2001.