Infectious Disease and Drug Discovery/Delivery
Faculty Biographies and Research Interests |
Erik Barton The Barton research program focuses on immunity during lifelong herpesvirus infection. The eight known human herpesviruses cause diseases including cold sores, blindness, chicken pox, infectious mononucleosis, and cancer. Herpesviruses are unique in their ability to persist in vivo in a non-replicating state referred to as latency, from which the virus can periodically reactivate to produce infectious progeny and recurrent disease. Because of the capacity of these viruses to evade the immune response and remain with the person for life, these pathogens are the focus of intense immunologic research. However, it is still largely unclear how herpesvirus latency is maintained, and what the physiologic consequences of viral latency are for the infected cell and organism.
Dr. Barton’s lab uses the murine gammaherpesvirus 68 (γHV68) system to address these questions and improve our understanding of the immune response to latent herpesvirus infection. γHV68 is a natural pathogen of mice and is closely related to the human herpesviruses Epstein-Barr virus (EBV, which causes mononucleosis) and Kaposi’s sarcoma herpesvirus (KSHV, which causes AIDS-associated tumors). The γHV68 model has four key advantages for studies of immunity to chronic virus infection: i) γHV68 can be easily mutated; ii) its genetic similarity to human herpesviruses has established it as a model system for exploring basic mechanisms of gammaherpesvirus infection, immunity, and cancer biology; iii) it encodes several genes that are predicted to modify cellular signaling pathways or evade the immune response; and iv) many knockout and transgenic mice with defined immune deficiencies are available, and novel mutant mice can be produced with relative ease.
Dr. Barton’s current research uses genetic and cell biological approaches to dissect mechanisms of immune function during γHV68 infection. They specifically focused on understanding the role of interferons (a key antiviral cytokine family secreted during virus infection) in regulating
latent virus infection, and the effects of prolonged interferon expression during latency
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Jean Chmielewski The Chmielewski research program focuses on the development of chemical entities for both drug discovery and the cellular delivery of therapeutic agents. Research in drug discovery centers on the identification of biologically active agents through either a rational design approach or from compound library screening and optimization. Current targets in this area are the protein-protein interactions of HIV, the pore forming toxins of pathogenic bacteria such as B. anthracis and S. aureus, and the human ABC transporter P-glycoprotein—a membrane bound protein that is responsible for multidrug resistance in cancer and limits the penetration of a wide range of therapies into the brain. Research in the area of drug delivery is centered on the development of scaffolds to allow delivery of therapeutics into specific cells. Cell penetrating polyproline and dendrimer scaffolds have promoted the facile entry of small molecule therapies and therapeutic biopolymers into cells, whereas folate-conjugated hydrogel nanoparticles displayed specific toxicity for cancer cells displaying the folate receptor.
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Arun Ghosh The Ghosh research group is involved in multidisciplinary research projects in the areas of synthetic organic, bioorganic and medicinal chemistry. Of particular interest, they are investigating the synthesis and biological studies of bioactive natural products and structure-based design of enzyme inhibitors for Alzheimer’s disease and AIDS. For instance, using computer-aided drug design, the Ghosh lab specifically designed and synthesized an agent to combat drug resistant HIV. These studies successfully led to the production of Darunavir—a therapy recently approved by the US FDA to treat drug resistant HIV. Along similar lines, the Ghosh lab is using computer-aided design to target a key enzyme, memapsin 2, involved in Alzheimer’s disease. Two designed agents were shown to be highly potent against memapsin 2, and this work represents the first case of designed potent inhibitors for this important pharmaceutical target related to Alzheimer's disease.
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Richard Kuhn The Kuhn research program focuses on understanding the biology of viruses that infect humans. Specifically, his lab is interested in viruses that contain a lipid bilayer membrane and contain plus strand RNA as their genetic material. These viruses are grouped in the Togaviridae and Flaviviridae families; some representative members include Sindbis, Ross River and Venezuelan equine encephalitis virus for Togaviruses, and yellow fever, dengue, West Nile and hepatitis C virus for the Flaviviruses. Viruses within these two groups pose significant risks to large segments of the population, and methods for controlling infection and disease are few. The Kuhn group’s goal is to understand all aspects of their replication cycle at the molecular level by integrating techniques from molecular genetics, biochemistry and structural biology.
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Cynthia Stauffacher The Stauffacher lab applies x-ray crystallography and molecular biology to systems where proteins work together in membranes to perform a biological function. Cholesterol production in humans begins with the activity of the membrane-associated enzyme, HMG-CoA reductase. They determined the structure of a bacterial analogue of this enzyme. Insights into the mechanisms of activation and inhibition have been gained by also determining the structure in the presence of substrates and the cholesterol-lowering drug Lovastatin, and lead to the possibility for design of new drugs to lower cholesterol.
ABC-transporters are ubiquitous membrane protein transport systems and include medically important molecules involved in multidrug resistance and cystic fibrosis. They have solved the atomic structure of a portion of one of these proteins. An examination of the complexes with substrates suggests a unique mechanism that links the energy from ATP cleavage with the physical opening and closing of a protein pore through the membrane. Some proteins they study are soluble, but have their effect at a membrane surface. An example is a pathogenic bacterium’s toxin that specifically binds to the surface of immune cells and stimulates them to grow and divide. By analyzing the structure of both wild type and mutant toxins, they have determined how the critical portions of the toxin protein interact with receptors on the immune cells.
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David Thompson Liposomes that efficiently release their contents within the cytoplasm of target cells are of great interest for cell biology, pharmaceutical, and gene therapy applications. Unfortunately, the potencies of many liposome-based formulations are curtailed by inefficient escape of the encapsulated contents following target cell uptake. The Thompson group has developed plasma-stable liposomes that rapidly and efficiently release their contents from endosomal compartments. The acid-catalyzed and photooxidative cleavage reactions that greatly enhance membrane permeability in these systems have been used to deliver water-soluble drugs, photosensitizers, and plasmids to target cells. These results suggest that concurrent application of selective targeting and membrane translocation mechanisms in liposomal drug carriers can greatly increase their efficacy. Molecular design, synthesis, kinetic studies, and tissue culture techniques are employed in their efforts to develop novel materials that promote efficient liposome-cell membrane fusion and intracellular drug delivery.
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