HOST-PATHOGEN INTERACTION IN VIRAL REPLICATION

医生科学家的职业发展需要一个广泛的方法，在学术医学与研究，教学和临床责任的职业生涯做准备。 该补助金提出了一个为期四年的职业发展计划，主要包括有针对性的假设驱动的研究，但也包括教学和辅导活动，参加机构和国家会议和会议，并继续临床培训。 威斯康星大学麦迪逊分校提供了理想的环境来发展作为一个医生科学家的职业生涯，以一流的医疗保健和尖端的生物医学研究，最先进的设施，广泛的技术和智力资源，以及研究人员和临床医生之间开放合作的强大传统而闻名。 拟议的研究将调查病毒复制和发病机制中涉及的动态和复杂的宿主-病原体相互作用。 正链RNA病毒的简单基因组结构和实验证据表明，宿主因子是其复制不可或缺的，尽管这些宿主因子的身份及其对病毒复制的功能影响在很大程度上仍然未知。 最近开发的新的病毒复制系统，在充分研究的酵母酿酒酵母允许参与正链RNA病毒复制的细胞宿主因子的功能研究。鸡群舍病毒（FHV）是一种双链正链RNA病毒，属于野大卫病毒科，是唯一能在猪链球菌中复制的动物病毒。因此代表了研究病毒复制机制的独特模型。 色葡萄酿酒酵母实验系统将用于分离和表征不能支持FHV复制的酵母突变体。 同时免疫化学方法也将用于分离和表征与FHV RNA聚合酶相关的细胞宿主蛋白。 宿主-病原体相互作用的鉴定和表征，特别强调细胞宿主因子的影响，对于理解病毒复制和发病机制的基本机制以及设计合理的抗病毒治疗都是至关重要的。

The career development of physician-scientists requires a broad approach in preparation for a career in academic medicine with research, teaching, and clinical responsibilities. This grant proposes a four-year career development plan consisting primarily of targeted hypothesis-driven research, but also incorporating teaching and mentoring activities, participation in institutional and national conferences and meetings, and continued clinical training. The University of Wisconsin-Madison provides the ideal environment to develop a career as a physician-scientist, with a reputation for premiere medical care and cutting-edge biomedical research, state-of-the-art facilities, extensive technical and intellectual resources, and a strong tradition of open collaboration among researchers and clinicians. The proposed research will investigate the dynamic and complex host-pathogen interactions involved in viral replication and pathogenesis. The simple genomic structure of positive-strand RNA viruses and experimental evidence suggest that host factors are indispensable for their replication, although the identity of these host factors and their functional impact on viral replication remain largely unknown. The recent development of novel viral replication systems in the well-studied yeast Saccharomyces cerevisiae permits the functional investigation of the cellular host factors involved in positive-strand RNA virus replication. Flock house virus (FHV), a bipartite positive-strand RNA virus and member of the Nodaviridae family, is the only animal virus shown to replicate in S. cerevisiae, and consequently represents a unique model to investigate the mechanisms of viral replication. The S. cerevisiae experimental system will be used to isolate and characterize yeast mutants unable to support FHV replication. A concurrent immunochemical approach will also be used to isolate and characterize cellular host proteins associated with the FHV RNA polymerase. The identification and characterization of host-pathogen interactions, with a particular emphasis on the impact of cellular host factors, are crucial both to understand the basic mechanisms of viral replication and pathogenesis and to design rational antiviral therapies.