Viral inclusion bodies and aggresomes: form and function

描述(申请人提供)：约翰·帕克博士是康奈尔大学分子病毒学博士，DVM研究科学家。帕克博士目前是哈佛医学院马克斯·尼伯特实验室的博士后研究员(NRSA F32 AI10134)。Nibert博士是本次MCSDA的发起人，是呼肠孤病毒分子病毒学领域国际公认的领导者，作为研究导师有着良好的记录。帕克博士近期的职业目标是在病毒致病的细胞和分子生物学方法方面获得高级培训。这次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，应该有助于他实现成为一名独立的、在全国具有竞争力的兽医研究科学家的长期职业目标。这些目标将在本MCSDA要求的三年期间内实现，方法是为Parker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方面的先进技术的机会。此外，在拟议的MCSDA过程中，Parker博士将在与赞助商协商后，承担更多关于该研究项目方向的决定责任。这种责任，再加上研究成果的书面和口头陈述方面的进一步经验，将为帕克博士提供独立研究生涯所需的工具。培训和研究将在系内进行。他是哈佛医学院微生物学和分子遗传学教授，是世界上最顶尖的生物医学研究机构之一。该研究计划将测试这样一种假设，即在受呼肠孤病毒感染的细胞中形成的病毒包涵体(Vlb)与细胞错误折叠的蛋白质反应共同作用，以便从一般细胞环境中浓缩和隔离病毒蛋白质和RNA，从而促进病毒的复制和组装，并诱导细胞病理学。特别是，这项研究计划将检查vlb的形态发生及其与微管和中间细丝的相互作用。在帕金森氏症和亨廷顿病等神经退行性疾病患者的神经元中发现的vlb和包涵体(侵袭体)之间的惊人相似之处将被探索。与vlb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病理生理效应相同。这项研究将极大地促进我们对病毒和神经退行性疾病中细胞病理学和疾病是如何通过细胞内包涵体的形成而诱发的理解。

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.