The Jun O. Liu Laboratory tests small molecules to see if they react in our bodies to find potential drugs to treat disease. We employ high-throughput screening to identify modulators of various cellular processes and pathways that have been implicated in human diseases from cancer to autoimmune diseases. Once biologically active inhibitors are identified, they will serve both as probes of the biological processes of interest and as leads for the development of new drugs for treating human diseases. Among the biological processes of interest are cancer cell growth and apoptosis, angiogenesis, calcium-dependent signaling pathways, eukaryotic transcription and translation.

The long-term goal of the Caren L. Freel Meyers Laboratory is to develop novel approaches to kill human pathogens, including bacterial pathogens and malaria parasites, with the ultimate objective of developing potential therapeutic agents. Toward this goal, we are pursuing studies of bacterial isoprenoid biosynthetic enzymes comprising the methylerythritol phosphate (MEP) pathway essential in many human pathogens. Studies focus on understanding mechanism and regulation in the pathway toward the development of selective inhibitors of isoprenoid biosynthesis. Our strategies for creating new anti-infective agents involve interdisciplinary research in the continuum of organic, biological and medicinal chemistry. Molecular biology, protein expression and biochemistry, and synthetic chemistry are key tools for our research.

Research in the Bradley Undem Lab centers around the hypothesis that the peripheral nervous system is directly involved in the processes of inflammation. This hypothesis is being studied primarily in the central airways and sympathetic ganglia. We are addressing this in a multidisciplinary fashion, using pharmacological, electrophysiological, biochemical and anatomical methodologies.

The Marshall Shuler Laboratory aims to understand the means by which brain reward systems convey reward value, expectancy, quality, probability and utility, and the rules by which such activity is used to affect synaptic weight within brain networks to encode stimulus-action associations. We use an interdisciplinary approach combining multisite recordings of neural activity, targeted pharmacological manipulation, viral-mediated gene transfer and behavior to study the neural mechanisms of reward-based interval learning in the primary visual cortex.

The Theresa Shapiro Laboratory studies antiparasitic chemotherapy. On a molecular basis, we are interested in understanding the mechanism of action for existing antiparasitic agents, and in identifying vulnerable metabolic targets for much-needed, new, antiparasitic chemotherapy. Clinically, our studies are directed toward an evaluation, in humans, of the efficacy, pharmacokinetics, metabolism and safety of experimental antiparasitic drugs.

Research in the Robert Siliciano Laboratory focuses on HIV and antiretroviral therapy (ART). ART consists of combinations of three drugs that inhibit specific steps in the virus life cycle. Though linked to reduced morbidity and mortality rates, ART is not curative. Through our research related to latently infected cells, we've shown that eradicating HIV-1 infection with ART alone is impossible due to the latent reservoir for HIV-1 in resting CD4+ T cells. Our laboratory characterized the different forms of HIV-1 that persist in patients on ART. Currently, we are searching for and evaluating drugs that target the latent reservoir. We are also developing assays that can be used to monitor the elimination of this reservoir. We are also interested in the basic pharmacodynamic principles that explain how antiretroviral drugs work. We have recently discovered why certain classes of antiretroviral drugs are so effective at inhibiting viral replication. We are using this discovery along with experimental and computational approaches to develop improved therapies for HIV-1 infection and to understand and prevent drug resistance. Finally, we are studying the immunology of HIV-1 infection, and in particular, the ability of some patients to control the infection without ART.

Research in the Craig W. Hendrix Lab concentrates on the chemoprevention of HIV infection, clinical pharmacology of antiviral drugs, drug interactions, and oral, topical and injectable HIV microbicide development. Our lab conducts small, intensive sampling studies of PK and PD of drugs for HIV prevention with a focus on developing methods to better understand HIV and drug distribution in the male genital tract, female genital tract and lower gastrointestinal tract. We also support numerous HIV pre-exposure prophylaxis development studies from phase I to phase III, largely as leader of the Pharmacology Core Laboratory of both the Microbicide Trial Network and HIV Prevention Trials Network.

A. Laboratory activities include the use of accelerator mass spectrometry (AMS) techniques to measure intracellular drugs and drugs metabolites. AMS is a highly sensitive method for detecting tracer amounts of radio-labeled molecules in cells, tissues, and body fluids. We have been able to measure intracellular zidovudine triphosphate (the active anabolite of zidovudine) in peripheral blood mononuclear cells from healthy volunteers given small doses of 14C-zidovudine, and have directly compared the sensitivity of AMS to traditional LC/MS methods carried out in our laboratory. B. Clinical research activities investigate the clinical pharmacology of new anti-HIV therapies and drug combinations. Specific drug classes studied include HIV reverse transcriptase inhibitors, protease inhibitors, entry inhibitors (selective CCR5 and CXCR4 antagonists), and integrase inhibitors. Scientific objectives of clinical studies include characterization of early drug activity, toxicity, and pharmacokinetics. Additional objectives are characterization of pathways of drug metabolism, and identification of clinically significant harmful and beneficial drug interactions mediated by hepatic and intestinal cytochrome P450 isoforms.

The Seth Blackshaw Lab uses functional genomics and proteomics to rapidly identify the molecular mechanisms that regulate cell specification and survival in both the retina and hypothalamus. We have profiled gene expression in both these tissues, from the start to the end of neurogenesis, characterizing the cellular expression patterns of more than 1,800 differentially expressed transcripts in both tissues. Working together with the lab of Heng Zhu in the Department of Pharmacology, we have also generated a protein microarray comprised of nearly 20,000 unique full-length human proteins, which we use to identify biochemical targets of developmentally important genes of interest.