Biography
Dr. Rosenthal is a Professor of Medicine at the University of California, San Francisco. He is a member of the Biomedical Sciences Graduate Program, the Sandler Center for Basic Research in Parasitic Diseases, and the Global Health Sciences Program at UCSF. He also directs a Fogarty International Center UCSF/Makerere University Training Grant for the training of African clinician scientists in malaria research. Dr. Rosenthal received a B.S. in Biochemistry from the State University of New York at Stony Brook and an M.D. from New York University. He then trained in Medicine at the University of Michigan and in Infectious Diseases at the University of California, San Francisco. He also served as a consultant for the World Health Organization. Dr. Rosenthal's research interests focus on malaria, including basic science, clinical, and translational research. Basic science studies include the characterization of a family of parasite cysteine proteases that includes promising targets for new antimalarial drugs. In collaboration with chemistry collaborators, his group is now pursuing drug discovery directed against cysteine proteases. Another project is exploring antibiotics as antimalarial drugs. Dr. Rosenthal's group also evaluates the clinical and molecular epidemiology of malaria, with studies based in Uganda. These studies include clinical trials of new antimalarial agents and drug combinations, evaluations of the roles of parasite and host genetic polymorphisms in drug resistance, considerations of the importance of the complexity of malaria infections, and studies of molecular mechanisms of drug resistance. Dr. Rosenthal is on the editorial boards of Antimicrobial Agents and Chemotherapy and The American Journal of Tropical Medicine and Hygiene. He has received an NIH Physician Scientist Award and was an Established Investigator of the American Heart Association. He receives research funding from the National Institutes of Health, the Centers for Disease Control and Prevention, and the Medicines for Malaria Venture.
Abstract
Translational Studies of Antimalarial Drug Resistance
Malaria is one of the greatest infectious disease problems in the world, and its control is severely limited by drug resistance. A better understanding of mechanisms of antimalarial drug resistance is greatly needed, but few groups are equipped to perform the translational studies needed to answer many key questions. We have been engaged in basic malaria research since the late 1980s and in clinical studies of antimalarial drug efficacy and resistance in Uganda since the late 1990s. This project will bridge our ongoing basic science and clinical malaria research programs to perform translational studies of antimalarial drug resistance. Tied to our research will be a major training effort, with mentoring of American junior faculty, postdoctoral fellows, and medical students and Ugandan junior scientists in translational malaria research. The broad objectives of our program will be to perform cutting edge translational research on malaria, primarily focusing on antimalarial drug resistance, to support the development of American clinical scientists with expertise in translational malaria research, and to support the development of African clinical scientists. In this research project we will test the hypotheses that the rate of antimalarial drug resistance development is dependent on the complexity and diversity of infections, that resistance develops due both to the migration of resistant clones and the spontaneous selection of resistant mutants, and that specific molecular mechanisms of resistance can be identified using modern molecular techniques.
Our specific aims will be as follows:
(1) Assessment of associations between the complexity and diversity of malaria infections and treatment outcomes. We will use samples from prior and ongoing clinical studies in Uganda to test the hypothesis that increased parasite complexity in an individual and diversity in a community favors the selection of drug-resistant parasites.
(2) Characterization of the selection of drug resistant malaria parasites. We will study laboratory isolates selected for resistance and isolates from patients with sensitive and resistant clinical outcomes to study the steps that lead to the elaboration of antimalarial drug resistance, in particular the relative contributions of migration of resistant clones into a community and the spontaneous selection of resistant parasites in an individual.
(3) Determination of molecular mechanisms of antimalarial drug resistance. We will compare sensitive and resistant laboratory and clinical isolates to evaluate putative resistance-mediating genes, including enzyme targets and potential drug transporters, and we will use genomic and proteomic techniques to screen for alterations that accompany drug resistance. Our project will provide important insights into mechanisms of antimalarial drug resistance and help to train a much-needed new generation of translational malaria researchers.