News and Publications

2002 DEPARTMENT HIGHLIGHTS

Professor Francis Chisari, M.D., was elected to membership in the National Academy of Sciences. Chisari joins Molecular and Experimental Medicine colleagues Professor Bernard Babior, M.D., Ph.D., Chair Ernest Beutler, M.D., and Professor Peter Vogt, Ph.D., as a recipient of this honor. Chisari was also elected to Fellowship in the American Academy of Microbiology in recognition of excellence, originality, and creativity in the microbiological sciences, joining fellow investigators Professor James Hoch, Ph.D., and Professor Eng Tan, M.D.

Professor Eric F. Johnson, Ph.D., won the 2002 Bernard B. Brodie Award in Drug Metabolism from the American Society for Pharmacology and Experimental Therapeutics for outstanding original research contributions in drug metabolism and disposition.

Professor Zaverio M. Ruggeri, M.D., received the Ercole Pisello Award from the Associazione Giuseppe Corradi in Bevagna, Italy. The prize honors an exceptional individual whose contributions are "of high relevance in the medical and scientific field."

Professor Eng Tan, M.D., was the recipient of the Western Society for Clinical Investigation's 2002 Mayo Soley Award, presented annually to an investigator in the Western United States who has made original and important contributions to research.

2002 RESEARCH HIGHLIGHTS

BIOCHEMISTRY

Division head: Professor Bernard Babior, M.D., Ph.D.

Professor Peter J. Sims, M.D., Ph.D., and Associate Professor Therese Wiedmer, Ph.D., focused on the biology of phospholipid scramblases, a family of proteins implicated in growth factor signaling. Aberrant expression may play a role in tumor formation and increased susceptibility to viral infection.

Associate Professor TakaoYagi, Ph.D., studied the mechanism of respiration that takes place in mitochondria, the powerhouses of living organisms. Dysfunction of respiration in mitochondria causes aging, neurodegenerative diseases (such as Parkinson's disease, amyotrophic lateral sclerosis), and cell death.

Babior's laboratory is studying oxygen metabolism in white blood cells. These cells manufacture reactive oxidants that they use to kill bacteria important for protection against infection.

The Johnson laboratory is directed toward understanding how the structural diversity and regulation of human P450 enzymes determine an individual's ability to avoid the adverse effects of exogenous chemicals.

Assistant Professor Xiaohua Wu, Ph.D., is determining the mechanisms underlying DNA damage repair and cell-cycle checkpoint control and addressing how genome stability is maintained, with the goal of providing insight into the molecular bases of diseases associated with genome instability and cancer.

CELLULAR BIOLOGY

Division head: Professor James Hoch, Ph.D.

Associate Professor Marta Perego, Ph.D., and Research Associate Lynn Hancock, Ph.D., individually mutated the genes for every two-component signal transduction system in pathogenic Enterococcus faecalis strains. They discovered the signaling systems that regulate biofilm persistence, antibiotic resistance, and structural stability of the bacterium.

Research Associate Haiyan Zhao, Ph.D., Associate Professor Kottayil Varughese, Ph.D., and Hoch added to our understanding of mechanisms of signaling by successfully obtaining a co-crystal of the Spo0A response regulator transcription factor with its DNA regulatory site. Spo0A controls anthrax toxin synthesis and other pathogenesis genes in Bacillus anthracis and may provide a target for the design of anti-anthrax agents.

EXPERIMENTAL HEMOSTASIS AND THROMBOSIS

Division head: Professor Zaverio Ruggeri, M.D.

Several studies are underway to improve understanding of the diseases that cause excessive blood loss or result in blood clots that occlude arteries and veins and cause heart attack, stroke, and emboli in the lungs.

Assistant Professor Brunhilde Felding-Haberman, Ph.D., is investigating how interactions of tumor cells with normal blood and vascular cells can favor the spreading of cancer. Other efforts by Associate Professor Daniel Salomon, M.D., and colleagues have been directed toward demonstrating the risks of the transplantation of animal organs into humans.

EXPERIMENTAL PATHOLOGY

Division head: Professor Francis Chisari, M.D.

Chisari's group demonstrated that interferon inhibits hepatitis B virus replication by activating an enzyme system in the infected cells that usually degrades misfolded cellular proteins. The team also found that interleukin-18 and activated macrophages inhibit hepatitis B virus replication. In collaboration with the Schultz lab, the Chisari group also identified the cellular genes likely to mediate the immune response for control of hepatitis B virus (HBV) and hepatitis C infections.

Assistant Professor Luca G. Guidotti, D.V.M., Ph.D., investigated the immunopathological mechanisms responsible for liver damage during HBV infection. Using HBV transgenic mice, the laboratory studied how antigen non-specific inflammatory cells are recruited into the liver by chemokines and other factors and how these cells enhance the liver disease initiated by antigen-specific cytotoxic T lymphocytes.

HEMATOLOGY

Division head: Chair Ernest Beutler, M.D.

Beutler's laboratory completed the largest-ever DNA-based population study (41,000 samples) in collaboration with Kaiser Permanente Hospital in San Diego of mutations causing hemochromatosis--a metabolic disorder in which excess deposits of iron occur in the liver, pancreas, and other organs. Surprisingly, even people who are homozygous for the mutation that causes hemochromatosis rarely manifest the disease. These findings may lead to a reassessment of widespread screening.

The laboratory of Associate Professor Roberta Gottlieb, M.D., showed that much of the damage produced in heart attacks is due to the activity of a family of enzymes known as cytochrome P450 mono-oxygenases, or CYP enzymes, which can produce excessive amounts of reactive oxygen species during reperfusion. In models, the lab showed that inhibition of CYP enzymes after the occlusion of a blood vessel could substantially reduce the severity of a heart attack. This approach holds promise for humans.

ONCOVIROLOGY

Division head: Professor Peter Vogt, Ph.D.

The Vogt laboratory, in collaboration with the laboratory of Professor Dale Boger, Ph.D., (Chemistry) isolated small molecule inhibitors of the Myc oncoprotein, which is causally involved in numerous human cancers and functions by binding to a partner protein, Max. These small molecule inhibitors inhibit the interaction of Myc with its obligatory partner Max and thus interfere with tumor-producing activity.

The laboratory of Associate Professor Dong-Er Zhang, Ph.D., has discovered the first protease (UBP43) involved in the regulation of protein ISG15 modification. Protein ISG15 conjugation is strongly increased upon viral and bacterial infection.

RHEUMATOLOGY

Division head: Professor Joel Buxbaum, M.D.

Tan continued to extend his analyses of autoantibodies from inflammatory to malignant disease, demonstrating an increase in both the frequency and specificity of autoantibodies in certain types of malignancies and suggesting that such analyses might be useful in cancer diagnosis.

Assistant Professor Zhixing Pan, M.D., Ph.D., Associate Professor Michael Robertson, Ph.D., and Associate Professor Bruce Zuraw, M.D., collaboratively and individually identified interactions between ligands and their receptors and the subsequent signaling pathways involved in specific inflammatory and allergic responses.

Associate Professor Michael Pollard, Ph.D., in collaboration with Associate Professor D.H. Kono, Ph.D., (Immunology) and investigator Per Hultman (Linkoping University, Sweden), used models lacking a gene with a known function in the immune-inflammatory pathway to show the requirement for particular genes in generating an autoimmune response to an environmental agent--in this case mercury.

Buxbaum and collaborators in Portugal showed that, in a disorder dependent on a mutation in a single gene that produces a dysfunctional protein, the age of onset of the disease may depend upon the interaction of a number of other apparently normal genes unlinked to the gene carrying the primary mutation.