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

病毒-受体相互作用在确定诺如病毒体内趋向性和发病机制中的作用

• 批准号: 9791682
• 负责人: Craig Brian Wilen
• 金额: $ 18.84万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-15 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9791682
• 关键词: Acute; Address; Advisory Committees; B-Lymphocytes; Basic Science; Binding; Biochemical; Biological Models; Biology; Bone Marrow; CRISPR screen; Cell Culture System; Cell Line; Cells; Cellular Tropism; Cellular biology; Cessation of life; Chronic; Clinical Pathology; Core Facility; Coupled; Dendritic Cells; Department chair; Diamond; Disease; Disease Outbreaks; Disease susceptibility; Doctor of Medicine; Doctor of Philosophy; Economics; Enrollment; Enteral; Environment; Faculty; Fostering; Gastroenteritis; Genes; Genetic; Genetic Predisposition to Disease; Genome; Goals; Hospitals; Human; IL10 gene; Immune system; Immunity; Immunodeficient Mouse; Immunology; Infection; Inflammation; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Integral Membrane Protein; Integration Host Factors; Intestines; Knockout Mice; Knowledge; Manuscripts; Medical; Mentors; Methods; Molecular Biology; Mus; Natural Immunity; Norovirus; Oral; Pathogenesis; Pathology; Pennsylvania; Phospholipids; Physicians; Play; Process; Program Development; Property; Records; Research; Research Infrastructure; Residencies; Resources; Role; Route; Science; Scientist; Shapes; Signal Transduction; Structural Protein; Susceptibility Gene; Testing; Time; Training; Training Programs; Tropism; Universities; Vaccines; Viral; Viral Gastroenteritis; Viral Pathogenesis; Viral reservoir; Virus; Virus Receptors; Washington; Work; antiviral immunity; career; career development; cell type; early onset; education resources; enteric infection; experience; experimental study; follower of religion Jewish; gastrointestinal; genome-wide; human model; immunoregulation; in vivo; insight; macrophage; member; mouse model; neutrophil; novel; prevent; protein structure; receptor; research facility; reverse genetics; skills; tool; transmission process; virome

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.

项目摘要/摘要 这份提案描述了一项为期五年的职业发展计划，该计划面向PI、Craig Wilen、M.D.、Ph.D. 目标是为他作为一名学术内科科学家的独立研究生涯做好准备。《少年派》 以优异成绩毕业于圣路易斯华盛顿大学，获得生物学和经济学学位。 然后，他在宾夕法尼亚大学参加了医学科学家培训计划，在那里他获得了 他拥有细胞和分子生物学的医学博士和博士学位。Wilen博士继续他作为住院医生的培训 巴恩斯犹太医院和华盛顿的临床病理医师科学家培训计划 大学。在实习期间，他在赫伯特博士的实验室从事基础科学研究 维珍，他将在这项提案中担任研究导师。维珍博士是 是华盛顿大学病理学和免疫学的一名经验丰富和富有成效的导师 内科科学家，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 这个实验室的博士后研究。 华盛顿大学提供优秀的教员、合作者和核心研究设施 这将促进Wilen博士的科学进步和职业发展。首先，Wilen博士的职业咨询 由戴蒙德、戈德堡、伦道夫和斯塔彭贝克博士组成的委员会拥有广泛的科学基础 与这项建议相关的专业知识，以及作为导师的非常成功的记录。第二，教育 包括博士后事务办公室和生物和生物医学科学司在内的资源将 使Wilen博士能够获得和发展更多的科学和专业技能。第三，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博士能够高效地 并巧妙地解决了这里所描述的科学目标。总而言之，华盛顿大学提供了 为Wilen博士发展和建立他的独立职业生涯提供理想的环境和资源 病毒与免疫系统相互作用导致疾病。 这项研究的长期目标是了解病毒-受体相互作用在 控制小鼠体内诺如病毒的嗜性和致病机制。小鼠诺如病毒是一种重要的 人类诺沃克病毒，这是全世界病毒性胃肠炎的主要原因。此外，小鼠诺如病毒 已被证明在具有某些遗传倾向的小鼠中会引发炎症性肠病。 然而，小鼠诺如病毒嗜性的决定因素和致病机制，以及病毒的致病机制。 诱导性肠炎仍不清楚。在Wilen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，鉴定CD300lf为小鼠诺如病毒的受体。Wilen博士是第一位联合 作者在描述这一发现的目前正在接受《科学》杂志审查的手稿上写道。这项工作具有重要的意义 对人类诺沃克病毒感染的影响，为研究诺沃克病毒提供了前所未有的机会 活体生物学。在这项提案中，我们将解决以下目标： 目的：1.我们将验证CD300lf对于MNoV体外感染是必要的和充分的假设 在活体内。 目的2.我们将检验CD300lf依赖的巨噬细胞、树突状细胞、 B细胞在MNoV体内致病机制中起不同作用。 这些研究将确定小鼠诺如病毒致病的新机制，这具有重要的意义 用于人类诺沃克病毒感染和肠道免疫。