Viral inclusion bodies and aggresomes: form and function

描述（由申请人提供）： 约翰·帕克医生是一名DVM拥有博士学位的研究科学家康奈尔大学的分子病毒学教授 帕克博士目前是哈佛医学院马克斯·尼伯特博士实验室的博士后研究员（NRSA F32 AI 10134）。本MCSDA的赞助人Nibert博士是国际公认的呼肠孤病毒分子病毒学领域的领导者，并作为研究导师有着良好的记录。 帕克博士的近期职业目标是获得病毒发病机制的细胞和分子生物学方法的高级培训。 这项培训将补充并大大拓宽他在分子病毒学方面的现有专业知识，再加上他作为兽医临床医生的经验，将有助于他实现成为一名独立的、具有全国竞争力的兽医研究科学家的长期职业目标。 通过为帕克博士提供学习应用于病毒-宿主相互作用研究的活细胞视频成像和蛋白质生物化学先进技术的机会，这些目标将在本MCSDA要求的三年期间实现。此外，在拟定的MCSDA期间，帕克博士将在与申办者协商后对本研究项目的方向承担更多的决策责任。 这种责任，加上进一步的经验，在书面和口头介绍的研究结果将给博士帕克的工具需要一个独立的研究生涯。 培训和研究将在该部进行。他是世界上最重要的生物医学研究机构之一哈佛医学院微生物学和分子遗传学系的主任。 该研究计划将测试这样的假设，即在呼肠孤病毒感染的细胞中形成的病毒包涵体（vlB）协同细胞错误折叠的蛋白质反应，以浓缩和隔离病毒蛋白质和RNA远离一般细胞环境，并通过这样做促进病毒复制和组装并诱导细胞病理学。 特别地，该研究计划将检查VIB的形态发生及其与微管和中间丝的相互作用。 将探索在患有神经变性疾病如帕金森病和亨廷顿病的患者的神经元中发现的vlB和包涵体（侵略体）之间的惊人相似性。 与vlB的发展相关的病理生理效应可能与神经退行性疾病中与包涵体形成相关的那些相同。这项研究应显着推进我们的理解，细胞病理学和疾病是如何在病毒和神经退行性疾病诱导细胞内包涵体的形成。

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.