The research activities of the Pharmacology Program are directed at understanding how drugs and chemicals modify biological systems. Drugs can act at many different levels of organization. At the level of gene expression Dr. Gudas is analyzing how derivatives of vitamin A (retinoids) regulate both cellular differentiation and cellular proliferation during development and in the process of tumor formation. Numerous retinoids are used clinically in cancer prevention and treatment. Dr. Xu has developed techniques to measure protein-protein interactions, and inhibitors of these interactions.  Dr. Sirotnak focuses on the molecular mechanisms of acquired resistance to antineoplastic agents which  has led to the discovery of a new and highly potent analog of methotrexate. Dr. Toth has identified a gene involved in epilepsy and is studying how dysfunction of this gene leads to this disease; he is also creating transgenic mouse models to study other types of neurological diseases.

Often the actions of drugs are mediated by specific receptors located on the cell surface or intracellularly. Dr. Pasternak is using molecular and biochemical techniques to characterize the receptors for analgesic drugs such as morphine. Dr. Inturrisi has found that NMDA receptor antagonists are able to prevent morphine tolerance and is examining how this receptor and the opioid receptors interact. Dr. Scheinberg is using monoclonal antibodies as drugs that specifically target sites on tumor cells, while Dr. Golde studies how cytokines regulate blood cell formation and the role of glucose transporters in neoplastic blood cells. Dr. Kraus studies the functions of the estrogen receptor and its role in gene transcription.

Receptors are linked to intracellular events by signal transduction pathways. Dr.Kolesnick has discovered a new signal transduction pathway, the sphingomyelin pathway, and is identifying how this pathway signals in response to receptor activation. Dr.'s Levin and Buck have discovered a new signaling pathway via an intracellular, soluble adenylyl cyclase. This signaling pathway plays a role in cell metabolism and in sperm activation. Many drugs interact with ion channels Dr. Gross is defining signal transduction processes involving nitric oxide, a reactive gas that is produced by mammalian cells and signals by chemical modification of protein targets. Nitric oxide plays a physiological role in regulating vascular function, host defense and neuronal signaling - too much nitric oxide appears to cause clinically important vascular disease, inflammation and neurodegeneration. Dr. Neil Harrison is studying how anesthetics interact with these channels. Dr. Geoff Abbott's research is focused on the functions of protein subunits of the potassium channels; mutations in some of these proteins lead to cardiac arrhythmia. At the cellular and sub-cellular levels, Dr. Levi is investigating transductional mechanisms of a novel histamine receptor subtype (the H3-receptor), which he discovered to be activated in myocardial ishcemia and affor cardioprotection. Dr. Rifkind is investigating how a cytoplasmic receptor for dioxin controls the expression of certain enzymes (cytochrome P-450s) and how this results in the diverse toxicities of dioxins and the polychlorinated biphenyls (PCBs). Dr. Buck has also characterized two new intracellular messenger molecules, 14-hydroxy-retro-retinol and anhydroretinol, and is studying their roles in the cell cycle and in malignant cells. Dr. Jaffrey is employing proteomics technology to develop a better understanding of the different proteins in various cell types. Such information could be used to develop blood tests for diseases in the future. Dr. Danishefsky's lab focuses on synthesizing new drugs for cancer therapy. Dr. Hemmings is interested in the critical role played by protein phosphorylation in the effects of general anesthetics on synaptic transmission,

Dr. Szeto is developing novel opioid drugs for use as obstetrical analgesics. The drugs are evaluated for their effects on the mother and the fetus. Dr. Felsen is examining the mediators of inflammation in the genitourinary tract, the receptors involved, and new drug therapies designed for renal and bladder diseases. Dr. Okamoto is involved in the development of new muscle relaxants for use during anesthesia. Dr. Reidenberg's clinical pharmacological studies are aimed at understanding the sources of variation in drug responses. He is evaluating the mechanisms of the antineoplastic and antifertility effects of gossypol.  Dr. Tan is developing diversity-oriented organic syntheses to identify new small molecule probes for studying biological systems.  Dr. Li is decoding molecular logic of intramembrane proteolysis that has emerged as a novel signaling paradigm, such as gamma-secretase-mediated signal transduction of APP, Notch and ErbB4.  Dr. Jaffrey uses molecular and chemical biology approaches to study RNA trafficking in neurons.  An additional focus of his laboratory is proteomics, the systematic identification and quantitation of proteins in a cell or tissue. Dr. Abbott recently discovered a family of potassium channel accessory submits and is investigating their ubiquity and necessity for generation of native potassium currents using electrophysiology and RNAi gene silencing.

More complete research descriptions can be found in Faculty Research Descriptions.

Updated 9/02