The Role of Rafts in Virus-Induced Membrane Remodeling

描述（由申请人提供）：申请人在物理学，光学和计算机方面有很强的定量背景，并对研究有浓厚的兴趣。在生物医学研究方法，特别是细胞生物学和假设驱动的科学的进一步培训，将使更广泛的跨学科的问题被攻击，并导致他成功地发展为一个独立的生物医学研究者。培训环境包括缅因州大学，那里的私人侦探。正在建设一个新的实验室和分子生物物理研究所。由于最近生物物理学的发展，该研究所与杰克逊实验室之间的跨学科联系，以及在美国获得第一台4Pi显微镜，在大学里有很多机会进行高度相关的生物医学研究合作、研讨会、讲习班和团队资助写作。对NIH的合作访问，导师在那里经营着一个完善的实验室，将为研究培训，与生物医学专家的互动以及获得设备提供极好的机会。 该研究计划的重点是病毒感染问题，这会导致相当大的死亡率。流感感染依赖于膜融合，这是通过蛋白质HA介导的胆固醇和鞘脂敏感机制，可能涉及微观膜簇称为筏。然而，这些领域的大小，形状，机制和动力学目前存在争议。该项目将使用新的，相对非侵入性的荧光光谱方法，以测试是否域的形式通过分区或HA和脂质之间的直接相互作用。该项目还将确定这些结构域在毫秒和微秒时间尺度上是静态的还是动态的，并测试细胞骨架是否介导细胞中的结构域大小或动态。由于筏动力学信息的缺乏，所提出的方法有一个不寻常的优势。结果将被用来试图更好地了解流感病毒是如何能够聚集自己的蛋白质出芽和进入（融合）。

DESCRIPTION (provided by applicant): 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).