Vaccines - Gregory A. Poland
The Vaccine Research Group (VRG) is organized under the Department of Medicine. Formally organized in 1989, the VRG was founded and is headed by Gregory A. Poland, M.D., and Dr. Robert Jacobson, M.D. The VRG mission is to improve the health of individuals across the world by pursuing challenges posed by infectious diseases and bioterrorism through clinical, laboratory and epidemiologic vaccine research. This group conducts NIH-funded research investigating the immunogenetics of vaccine response, tests, develops and studies vaccines for biodefense, and also conducts clinical studies of novel vaccines and adjuvants in adults and children. The VRG successfully combines laboratory facilities for immunologic testing and state-of-the-art immunogenetic techniques.
HIV-1 Replication, Lentiviral Vectors - Eric M. Poeschla
Our research interests are in the molecular pathogenesis of HIV disease/AIDS and in uses of lentiviral vectors in human gene therapy. This page contains a brief summary of our research. We investigate lentivirus biology to develop novel gene transfer vectors suitable for human gene therapy and to elucidate mechanisms of lentiviral (HIV) disease pathogenesis. Lentiviruses such as HIV-1 differ from other retroviruses in their ability to infect non-dividing cells in vivo; for example, HIV-1 infects terminally differentiated tissue macrophages in vivo. Lentiviral vectors exploit this ability to achieve stable integration in non-dividing cells. HIV-based and feline immunodeficiency virus (FIV)-based lentiviral vectors are being studied in our laboratory. Collaborations have also been developed with other investigators at Mayo and elsewhere to investigate lentiviral vector gene therapy. Several individuals in the laboratory are using the eye as a model system, with a focus on glaucoma gene therapy. We are interested in the molecular basis of HIV disease pathogenesis, and we are investigating functional interactions of integrase and other HIV-1 proteins with cellular factors (LEDGF/p75, HRP-2) and interactions of Gag proteins and viral RNA in genome packaging.
Hepatocellular Carcinoma - Lewis R. Roberts
The major goals of my laboratory are to understand the mechanisms by which liver cancers develop, grow and spread; with the goal of identifying the critical pathways needed for the growth of individual cancers and eventually being able to provide the necessary information so that a doctor treating a patient with liver cancer can select specific treatments targeted at the growth signaling pathways which are most critical for that individual patient's cancer and can tailor the treatment design to most effectively control or eliminate that specific cancer. This individualized or personalized medicine will allow effective treatment of cancer with minimal side effects.
The second goal of our laboratory is to develop and validate methods for early detection and diagnosis of primary liver, biliary and pancreas cancers.
Human Immunodeficiency Virus - Andrew D. Badley
The background and objectives of our laboratory are to define the interactions between infectious diseases and aberrant apoptosis regulation with an emphasis on pathogenesis and therapy. Recent examples include:
- Defining the mechanism by which HIV protease expression induces cell death, the activation off procaspase 8; HIV-1 protease processes procaspase 8 to cause mitochondrial release of cytochrome c, caspase cleavage and nuclear fragmentation; and HIV-1 protease cleaves procaspase 8 in vivo.
- Defining that a naturally occurring polymorphisms within Vpr (R77Q) have an impaired ability to induce cell death and that this polymorphism is associated with long-term non-progressive HIV; Vpr R77Q is associated with long-term nonprogressive HIV infection and impaired induction of apoptosis.
- Defining that HIV gp120 can cause the death of hepatocytes through CXCR4 receptor binding; Human immunodeficiency virus-induced apoptosis of human hepatocytes via CXCR4.
- Demonstrating that HIV infected resting memory T cells (latently infected) die in response to TRAIL receptor ligation, raising the possibility that such treatment might be used as a therapy for HIV; Induction of cell death in human immunodeficiency virus-infected macrophages and resting memory CD4 T cells by TRAIL/Apo2L; Differential effects of Interleukin-7 and Interleukin-15 on NK cell anti-Human Immunodeficiency Virus activity.
- Demonstration that HIV reactivation induced by TCR ligation requires both PKC and PKCq isoforms; HIV reactivation by phorbol esters or TCR ligation requires both PKCΑ and PKCθ.
- Demonstrating the observation and mechanism by which the HIV protease inhibitor class of drugs are intrinsically antiapoptotic both in vitro, and in vivo, and consequently improve survival in mouse models of hepatitis, sepsis, and stroke; Improved survival in experimental sepsis with an orally administered inhibitor of apoptosis; Inhibition of adenine nucleotide translocator pore function and protection against apoptosis in vivo by an HIV protease inhibitor.
- Defining the signal transduction pathway that occurs downstream of CXCR4 signaling by gp120 in order to result in cell death; gp120 binding to CXCR4 causes p38-dependent primary T cell death that is facilitated by, but does not require cell-associated CD4.
- Demonstrating that HIV protease inhibitors not only block viral replication in cells from HIV-infected patients, but also even in the face of antiviral resistance, HIV protease inhibitors exert anti-apoptotic effects which reduce cell death caused by HIV-associated proteins; Flying in the face of resistance: antiviral independent benefit of HIV protease inhibitors on T cell survival.
Anticancer Drug Action - Scott H. Kaufmann
Of the 1.4 million Americans diagnosed with cancer this year, roughly 600,000 will die of this group of diseases. If current chemotherapy or immunotherapy were effective, these patients would be cured of their neoplasms. Our laboratory is attempting to gain insight into the limited efficacy of current therapies by investigating the biochemical basis for killing by effective chemotherapeutic agents and cytotoxic lymphocytes as well as the mechanisms by neoplastic cells evade this killing. Apoptosis (programmed cell death) is a distinct form of cell death that occurs under a variety of physiological and pathological conditions. Building on earlier observations that a variety of chemotherapeutic agents induce apoptosis in susceptible cell types, members of my laboratory are investigating how the signaling by various components of apoptotic pathways is affected by changes in phosphorylation and other posttranslational modifications. At the same time, other members of my laboratory are using topoisomerase I poisons, which are used to treat a number of common cancers, as prototypic drugs to investigate changes further upstream that determine whether anticancer drugs are able to interact with their targets and trigger the signaling required to activate the cell death process. Finally, in conjunction with other members of the Developmental Therapeutics Program of the Mayo Clinic Cancer Center, we are examining the cytotoxic action of a number of novel anticancer agents in preclinical model systems and, in some cases, in the context of phase I and phase II clinical trials.
Infectious Diseases - Robin Patel
The Infectious Diseases Research Laboratory has a long history of education and innovation in vitro and in vivo investigations of unique antimicrobial therapies, novel patterns of antimicrobial resistance, emerging pathogens, mechanisms of antimicrobial resistance, and, most recently, biofilm-mediated infections. Culture-based methods, molecular techniques, animal models, and human studies are used. The origins of research in infectious diseases at Mayo can be traced to Dr. Wallace E. Herrell who, among other things, established the clinical efficacy and pharmacokinetics of penicillin. In 1943, he was the first to describe successful penicillin therapy for sulfonamide-resistant gonococcal arthritis (WE Herrell, EN Cook, L Thompson, Journal of the American Medical Association 1943;122:289-92). Dr. Herrell was also the last first assistant to Dr. Charles Mayo. Dr. Joseph E. Geraci later performed a series of landmark studies on bacterial endocarditis and was one of the first to work with the antibiotic vancomycin. The physical laboratory itself was founded circa 1981 by Dr. Walter R. Wilson who, among other accomplishments, worked with experimental animal models of endocarditis. Subsequent to Dr. Wilson, the laboratory was under the directorship of Dr. James M. Steckelberg, current Chair of the Division of Infectious Diseases. The laboratory’s present day focus is on microbial biofilms. Biofilms are a unique state of existence preferentially employed by microorganisms in most environments; they are involved in two thirds of human infections, rendering them of enormous public health relevance. Biofilms protect microorganisms from environmental stresses, currently available antimicrobial agents and host immune defenses. Understanding mechanisms of biofilm formation will enable novel therapeutic and preventive strategies for the recalcitrant diseases (e.g., prosthetic joint infection, endocarditis, catheter-associated infection) with which biofilms are associated. We have a series of studies ongoing wherein we are developing novel diagnostics for orthopaedic device-related infection. We are characterizing mechanisms of biofilm formation in the recently recognized pathogen, Staphylococcus lugdunensis. And, we are investigating novel approaches to the therapy of biofilm-mediated infections.
Robert Orenstein, D.O.
Dr. Orenstein is a consultant in the division of Infectious Diseases and an associate hospital epidemiologist in the section of Infection Prevention and Control where he develops educational resources in infection prevention and control for the physician and scientist staff at Mayo Clinic Rochester. He does not have a basic science laboratory but conducts investigations of infectious agents of clinical and epidemiological relevance. Recent projects have addressed the management of rabies and brucella exposures in the healthcare environment. He has worked with state and local public health authorities on several outbreaks of newly recognized illnesses including tattoo associated mycobacterial infections and the recently described polyneuropathy identified in swine slaughterhouse workers. He has extensive experience in the conduct of clinical trials of new anti-infective agents and antiretroviral therapies. In addition to the conduct of clinical trials, his recent laboratory projects have focused on the development of an electronic symptom watch to track laboratory associated brucellosis and melioidosis.
Melanoma - Svetomir N. Markovic, M.D., Ph.D.
Translational immunotherapeutics of cancer focused on malignant melanoma and non-Hodgkin's lymphoma. This work includes development and clinical testing of: cancer vaccines; immune boosting agents; novel agents that reconstitute immunity in patients with cancer; and combination therapy directed at enhancing anti-tumor immune responses.
Leslie T. Cooper, M.D.
Research involves clinical and translational studies regarding the autoimmune determinants of myocarditis and dilated cardiomyopathy.