Research Areas

Research efforts in cancer pharmacology include studies of the basic mechanisms of signal transduction associated with cell proliferation and apoptosis, the mechanisms of action of anti-neoplastic agents, the design and discovery of new drugs, basic mechanisms of DNA repair and DNA damage tolerance and the development of novel strategies for gene therapy

Emphasis is placed on the description and characterization of basic signaling mechanisms that constitute the targets of molecules used for cancer therapy and DNA damage and repair mechanisms that contribute to anti-neoplastic drug resistance. The regulation of tyrosine kinases, processing of proto-oncogenes, regulation of small GTPases and their effectors, cell-cycle-specific kinases and DNA repair gene products are being studied as potential targets or to enhance the efficacy of existing chemotherapeutic agents. The role of growth factors in the progression of solid and hematopoietic tumors is being studied; new receptors and signal transduction pathways are being identified in normal and malignant tissues.

Other areas of research include investigations on interleukin therapy, free radical generation, molecular mechanisms of antioxidant regulation and detoxification, aberrations in the mechanisms of programmed cell death (apoptosis) associated with tumoral growth and alterations in DNA repair and DNA damage response genes associated with tumor growth and chemotherapeutic resistance.

Drug Discovery is an emerging pharmacological science that seeks to identify novel small molecule probes and to understand at a molecular level how compounds affect macromolecular process. Cell-based, in vitro mix-and-read, and whole organism assays suitable for rapid or high throughput analysis are being designed and implemented by members of the Molecular Pharmacology Program. Current molecular targets include Gprotein coupled receptors, vanilloid receptors, cathepsins, apoptosis-inducing proteins, ion channels, steroid receptors, orphan nuclear receptors, kinases, phosphatases, DNA repair enzymes, and DNA polymerases. Chemical libraries and automated screening instrumentation are emphasized, which permit rapid interrogation of optimized assays. Computational approaches and high content cell screening methodologies are employed to facilitate the identification of new chemical probes.

The physiological basis of neuronal toxicity caused by various insults including excitatory amino acids, oxidative stress and cerebral ischemia is being studied using quantitative imaging techniques, confocal microscopy, genetic approaches in model organisms, and molecular approaches in cultured cell lines, cultured primary neurons and in intact animals. These studies aim to develop an understanding of the mechanisms of neuronal injury in acute and chronic disorders. The regulation of the expression of voltage-gated ion channels in cell lines and primary cultures is being studied by molecular and patchclamping techniques. In addition, molecular genetic, electrophysiological and cell biological approaches are being used to explore the relationships between neurotransmitter transporter structure, substrate transport, inhibitor binding and ion permeation. New quantitative imaging approaches are being used to study the basic processes of neuropeptide secretion. Investigators in the Molecular Pharmacology program are also examining the mechanisms of autonomic regulation and synaptic transmission of the urogenital system. These studies include neuroanatomical and neurophysiological research aimed towards the development of agents to modulate neuronal control of the urinary bladder, colon, and sex organs. Targeted disruption of GABA receptors is being used as a tool to investigate the function of these receptors and their specific components in transgenic mice. The mechanism of action of anesthetics is being studied in genetic model organisms and using techniques of magnetic resonance spectroscopy.

Investigators in the Molecular Pharmacology program are also examining the mechanisms of autonomic synaptic transmission and the autonomic regulation of the urogenital and renal systems. These studies include: 1) neuroanatomical and neurophysiological research aimed towards the development of agents to modulate neuronal control of the urinary bladder, colon, and sex organs; 2) biochemical/molecular analysis of the role of PP-fold peptides released from autonomic synaptic junctions in the regulation of renovascular tone and arterial blood pressure in genetic hypertension; and 3) the interaction between the sympathetic nervous system and estradiol on renal function.

The department is rich in research devoted to the analysis of signal transduction pathways and their role in normal physiological processes and disease. These include studies into the basic mechanisms of signaling by oxidizing and free radical inflammatory mediators, nitric oxide, steroids, parathyroid hormone, neurotransmitters, hypothalamic hormones, and rhodopsin. Various cell biological, forward and reverse genetic, molecular biological and biophysical approaches are used to dissect the molecular mechanisms utilized by intracellular mediators of signal transduction including cell surface receptors, nuclear receptors, caveolin, protein kinases, protein phosphatases and lipid kinases.