Role of virus-receptor interactions in determining norovirus tropism and pathogenesis in vivo

项目总结/摘要 该提案描述了PI，克雷格威伦，医学博士，博士到 目标是为他作为一名学术物理学家和科学家的独立研究生涯做好准备。的pi 以优异成绩毕业于圣路易斯的华盛顿大学，获得生物学和经济学学位。 然后，他参加了宾夕法尼亚大学的医学科学家培训计划， 医学博士学位和博士细胞与分子生物学威伦博士继续他的培训，作为一个住院医师， 巴恩斯-犹太医院和华盛顿的临床病理学医师科学家培训计划 大学在他的住院医生选修时间，他开始在赫伯特博士的实验室基础科学研究 维珍，谁将担任这项建议的研究导师。维珍博士是系主任 病理学和免疫学在华盛顿大学，是一个非常有经验和富有成效的导师， 他是一位医学科学家，也是病毒发病机制和免疫方面的领先专家。威伦医生将继续他的 在这个实验室做博士后研究 华盛顿大学提供优秀的教员、合作者和核心研究设施 能促进维伦博士的科学进步和事业发展第一，Wilen博士的职业咨询 委员会由钻石博士，戈德堡，兰多夫，和Stappenbeck具有广泛的科学 与本提案相关的专业知识和作为导师的成功记录。第二，教育 包括博士后事务办公室和生物学和生物医学科学部在内的资源将 使Wilen博士能够获得和发展额外的科学和专业技能。三是研究 维珍实验室和华盛顿大学核心设施内的基础设施将使Wilen博士能够有效地 并巧妙地解决了本文所述的科学目的。总之，华盛顿大学提供了 理想的环境和资源，博士Wilen发展和建立他的独立职业生涯研究如何 病毒与免疫系统相互作用导致疾病。 本研究的长期目标是了解病毒-受体相互作用在 在体内控制鼠诺如病毒的嗜性和致病性。鼠诺如病毒是一种重要的模型， 诺如病毒是全球引致病毒性肠胃炎的主要原因。此外，鼠诺如病毒 已被证明在具有某些遗传倾向的小鼠中引发炎症性肠病。 然而，小鼠诺如病毒嗜性和致病性的决定因素，以及病毒- 诱导的肠道炎症仍然未知。在维伦博士在维珍实验室的短暂时间里，他进行了一次 全基因组CRISPR筛选，将CD300lf鉴定为鼠诺如病毒的受体。威伦博士是共同第一 这篇论文的作者目前正在《科学》杂志上进行审查，他描述了这一发现。这项工作具有重要意义 这对人类诺如病毒感染的影响，并为研究诺如病毒提供了前所未有的机会。 体内生物学在本提案中，我们将致力于实现以下目标： 目标1.我们将检验CD300 lf对于MNoV离体感染是必要和充分的假设。 和体内。 目标二。我们将检验巨噬细胞、树突状细胞， 和B细胞在体内对MNoV的发病机制有不同的贡献。 这些研究将明确小鼠诺如病毒致病的新机制，具有重要意义 对于人类诺如病毒感染和肠道免疫两者。

Project Summary/Abstract This proposal describes a five-year career development program for the PI, Craig Wilen, M.D., Ph.D. to with the goal of preparing him for an independent research career as an academic physician-scientist. The PI graduated summa cum laude from Washington University in St. Louis with a degree in Biology and Economics. He then enrolled in the Medical Scientist Training Program at the University of Pennsylvania where he earned his M.D. and Ph.D. in Cell and Molecular Biology. Dr. Wilen continued his training as a resident physician in the Clinical Pathology Physician Scientist Training Program at Barnes-Jewish Hospital and Washington University. During his residency elective time, he embarked on basic science research in the lab of Dr. Herbert Virgin, who will serve as the research mentor in this proposal. Dr. Virgin is the Chair of the Department of Pathology and Immunology at Washington University and is a highly experienced and productive mentor of physician-scientists and a leading expert in viral pathogenesis and immunity. Dr. Wilen will continue his postdoctoral research in this lab. Washington University provides outstanding faculty members, collaborators, and core research facilities that will foster Dr. Wilen's scientific progress and career development. First, Dr. Wilen's Career Advisory Committee comprised of Drs. Diamond, Goldberg, Randolph, and Stappenbeck has extensive scientific expertise relevant to this proposal and highly successful track records as mentors. Second, the educational resources including the Office of Postdoctoral Affairs and the Division of Biology and Biomedical Sciences will enable Dr. Wilen to acquire and develop additional scientific and professional skills. Third, the research infrastructure within the Virgin lab and Washington University core facilities will enable Dr. Wilen to efficiently and skillfully address the scientific aims described herein. In summary, Washington University provides the ideal environment and resources for Dr. Wilen to develop and establish his independent career studying how viruses interact with the immune system to cause disease. The long-term goal of this study is to understand the role of virus-receptor interactions in governing murine norovirus tropism and pathogenesis in vivo. Murine norovirus is an important model for human norovirus, which is the primary cause of viral gastroenteritis worldwide. In addition, murine norovirus has been demonstrated to trigger inflammatory bowel disease in mice with certain genetic predispositions. However, the determinants of murine norovirus tropism and pathogenesis, and the mechanism of virus- induced enteric inflammation remain unknown. During Dr. Wilen's brief time in the Virgin lab, he performed a genome-wide CRISPR screen that identified CD300lf as a receptor for murine norovirus. Dr. Wilen is co-first author on a manuscript currently under review at Science describing this finding. This work has important implications for human norovirus infection and provides an unprecedented opportunity to study norovirus biology in vivo. In this proposal we will address the following aims: Aim1. We will test the hypothesis that CD300lf is necessary and sufficient for MNoV infection ex vivo and in vivo. Aim 2. We will test the hypothesis that CD300lf-dependent infection of macrophages, dendritic cells, and B cells differentially contributes to MNoV pathogenesis in vivo. These studies will define new mechanisms of murine norovirus pathogenesis, which has important implications for both human norovirus infection and enteric immunity.