Viral inclusion bodies and aggresomes: form and function

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DESCRIPTION (provided by applicant): Dr. John Parker is a D.V.M. research scientist with a Ph.D. in molecular virology from Cornell University. Dr. Parker is currently a post-doctoral fellow (NRSA F32 AI10134) at Harvard Medical School in Dr. Max Nibert's lab. Dr. Nibert, the sponsor of this MCSDA, is an internationally recognized leader in the field of reovirus molecular virology and has a strong track record as a research mentor. Dr. Parker's immediate career goal is to attain advanced training in cell and molecular biological approaches to viral pathogenesis. This training will complement and significantly broaden his existing expertise in molecular virology, which together with his experience as a veterinary clinician should help him achieve his longer-term career goal of becoming an independent, nationally competitive, veterinary research scientist. These goals will be achieved over the requested three year period of this MCSDA by providing Dr. Parker the opportunity to learn advanced techniques in live-cell video imaging and protein biochemistry as applied to the study of virus-host interaction. In addition, during the course of the proposed MCSDA, Dr. Parker will assume more responsibility for decisions regarding the direction of this research project after consultations with the sponsor. This responsibility, together with further experience in written and oral presentation of research findings will give Dr. Parker the tools needed for an independent research career. The training and research will take place in the Dept. of Microbiology and Molecular Genetics at Harvard Medical School, one of the foremost biomedical research institutions in the world. The research plan will test the hypothesis that the virus inclusion bodies (vlBs) that form in reovirus-infected cells co-opt the cellular misfolded protein response in order to concentrate and sequester viral proteins and RNAs away from the general cellular milieu and by so doing promote viral replication and assembly and induce cytopathology. In particular this research plan will examine the morphogenesis of vlBs and their interaction with microtubules and intermediate filaments. Striking similarities between vlBs and inclusion bodies (aggresomes) found in neurons of patients afflicted with neurodegenerative diseases such as Parkinson's and Huntington's disease will be explored. The pathophysiologic effects associated with the development of vlBs are likely to be the same as those associated with inclusion body formation in neurodegenerative disease. This research should significantly advance our understanding of how cytopathology and disease are induced during viral and neurodegenerative disease by the formation of intracellular inclusion bodies.