Select a year 2001 2002 2003    Select a researcher Alan G. Barbour, M.D. William Bishai, M.D., Ph.D. Martin J. Blaser, M.D. John C. Boothroyd, Ph.D. Jon Clardy, Ph.D. Peter Cresswell, Ph.D. Roy Curtiss, III, Ph.D. Ronald W. Davis, Ph.D. Jack E. Dixon, Ph.D. Stanley Falkow, Ph.D. Gerald R. Fink, Ph.D. Richard A. Flavell, Ph.D. Lee Gehrke, Ph.D. Laurie H. Glimcher, M.D. Jeffrey I Gordon, M.D. Daniel L. Hartl, Ph.D. William R. Jacobs, Jr., Ph.D. Keith A. Joiner, M.D., co-PI Karla Kirkegaard, Ph.D. Roberto G. Kolter, Ph.D. W. Ian Lipkin, M.D. Richard M. Locksley, M.D. Carl Nathan, M.D. Peter Palese, Ph.D. Pradipsinh K. Rathod, Ph.D. David A. Relman, M.D. Charles M. Rice, Ph.D. Alexander Rich, M.D. Lee W. Riley, M.D. David S. Roos, Ph.D. Abigail A. Salyers, Ph.D. Gary K. Schoolnik, M.D. Iwona Stroynowski, Ph.D. Ronald P. Taylor, Ph.D. Elisabetta Ullu, Ph.D. John Waitumbi, D.V.M., Ph.D Select a project A Gnotobiotic Zebrafish Model for Analyzing Symbiotic Host...Antiviral Effects of Interferon-Inducible Cytosolic ProteinsArming the Immune System against Pathogens with Selective ...Bacterial Pathogen Families that Function in Both the Anim...Cellular Genes and Viruses: Who Wins The War?Conditional Targeted Deletions in Plasmodium falciparum...Designing and Mining Pathogen Genome Databases: The Apicop...Development of Genetic Systems for Genetically Intractable...Development of New Genetic Tools to Identify Nutrient Upta...Ecological Influences on Pathogen Genome EvolutionEvolution of Virulence in Eukaryotic PathogensExploiting an Evolutionary Omission in Pathogenic RNA Viru...Exploring Novel Pathways of Immune Defenses Against Orally...Genomic Approach to Improved Immunogenicity of M. tuber...Genomic tools to characterize hypermutating Plasmodium fal...Investigation of Mechanisms Leading to Anemia at Low Paras...Molecular definition of the bacterial population of human ...Mycobacterium Tuberculosis Latency and Reactivation Tuberc...New Antibiotics from Environmental DNAOptimizing Immunity to Complex Pathogens In VivoPandora's Box ProjectProviding an Economic Benefit to Using a Vaccine to Enhanc...Resistance Gene Flow in the Human Colonic MicrofloraRole of Nucleotide Binding Domain-Leucine Rich Repeat Prot...Sexually Transmitted Disease Agents in the “Healthy” Human...Systematic Analysis of Positive-strand RNA Viral Transmiss...The Human Intestinal Microbiome: Community Analysis, Host ...The Molecular Ecology of Vibrio cholerae in the Gangetic D...The Natural History of Typhoid Infection in VietnamThe Role of Quorum Sensing in Fungal DiseaseTowards Broad-spectrum Antivirals: Functional Screens for ...Transmission Blocking Vaccines for TuberculosisTransmission-blocking Vaccines Against Arthropod VectorsViral Pathogenic Mechanisms Involving Z-DNA Binding Proteins Select an institution Albert Einstein College of Medicine of Yeshiva University Columbia University Harvard Medical School Harvard School of Public Health Harvard University Johns Hopkins School of Public Health Massachusetts Institute of Technology Mount Sinai School of Medicine New York University School of Medicine Rockefeller University Stanford University School of Medicine Stanford University School of Medicine, VA Palo Alto Health Care System University of California - Berkeley University of California - Irvine University of California - San Diego University of California - San Francisco University of Illinois - Urbana-Champaign University of Pennsylvania University of Texas Southwest Medical Center University of Virginia University of Washington Washington University Washington University School of Medicine Weill Medical College of Cornell University Whitehead Institute for Biomedical Research Yale University School of Medicine

Lee Gehrke, Ph.D. Massachusetts Institute of Technology

The identification of features that are pathogen-specific and sensitive to therapeutic agents is fundamental to treating infectious human diseases. This proposal focuses on a feature common to a wide range of pathogenic RNA viruses: the absence of poly(A) tails on the viral messenger RNAs. Viruses included in this group include dengue hemorrhagic fever, West Nile, Japanese and St. Louis encephalitis, and rotaviruses. We propose to define the molecular mechanisms enabling the viral mRNAs to circumvent the functional requirement for poly(A) tails that is shared among cellular mRNAs. The ultimate goal is to develop a unified approach for drug therapy.

Brief Description of Proposed Research: With exceedingly few exceptions, cellular messenger RNAs (mRNAs) terminate in poly(A) tails, which are now known to regulate the efficiency of cellular mRNA translation. RNA-protein and protein-protein interactions between the 5’ cap structure and the 3’ poly(A) facilitate ribosome binding during the initiation stage of protein biosynthesis. In contrast, the mRNAs of a number of pathogenic RNA viruses share a common feature that distinguishes them from cellular mRNAs: they lack 3’ poly(A) tails, yet are in fact stable and fully capable of supporting protein synthesis. Our goal is to define the common mechanism(s) that allow these viral mRNAs to circumvent the poly(A) requirement during mRNA translation. Our approach is two-fold. First, we propose to identify nucleotide sequences or structures in the 5' and/or 3' untranslated regions of the viral RNAs that both distinguish them from cellular mRNAs and release them from dependence on the poly(A) tail. Second, we propose to define RNA binding proteins that interact with these untranslated regions, thereby allowing them to translate efficiently without the poly(A) tail. This experimental strategy will provide important new insights into mechanisms of viral gene statement and will identify new targets for therapeutics to treat viruses that cause significant morbidity and mortality worldwide.

This proposal has three Specific Aims. The experiments will focus on the 5’ and 3’ untranslated regions of the viral mRNAs, which very likely contribute to the translation-level regulation. The first Specific Aim will be to use bioinformatics approaches to compare the 5’ and 3’ untranslated regions of the viral RNAs in an effort to identify nucleotide sequences or structures that may be related among this diverse group of viruses. The second Specific Aim will use genetic approaches to identify nucleotides that are required for efficient viral mRNA translation. The third Specific Aim will be to apply biochemical methods toward the identification of host factors and/or viral proteins that bind to the viral RNAs and influence translation.

Contact Dr. Gehrke.