The applicant has a strong quantitative background in physics, optics, and computers, and has strong interest in research. Further training in biomedical research methods, in particular cell biology and hypothesis-driven science, would enable a broader range of interdisciplinary problems to be attacked, and lead to his successful development as an independent biomedical investigator. The training environment includes the University of Maine, where the P.I. is building a new laboratory and the Institute for Molecular Biophysics. Due to a recent growth in biophysics, the interdisciplinary links between the Institute and the Jackson Laboratory, and the acquisition of the first 4Pi microscope in the U.S., there are many opportunities for highly relevant biomedical research collaborations, symposia, workshops, and team grant writing at the University. Collaborative visits to the NIH, where the mentor runs a well-established laboratory, will provide excellent opportunities for research training, interaction with biomedical experts, and access to equipment. The research plan focuses on the problem of viral infection, which causes considerable mortality. Infection by influenza depends on membrane fusion, which is mediated through the protein HA by a cholesterol- and sphingolipid-sensitive mechanism that likely involves microscopic membrane clusters called rafts. However, the size, shape, mechanism, and dynamics of such domains are currently disputed. This project will use novel, relatively noninvasive fluorescence spectroscopic methods to test whether domains form by partitioning or by direct interaction between HA and lipids. The project will also determine whether the domains are static or dynamic on millisecond and microsecond timescales, and test whether the cytoskeleton mediates domain size or dynamics in cells. Because information about raft dynamics is in shortage, the proposed methods have an unusual advantage. Results will be used to attempt to better understand how influenza virus is able to congregate its own proteins for budding and entry (fusion).
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