Novel Role of Enterovirus 71 VP4 in Modulation of Cell Death Pathways

肠道病毒 71 VP4 在调节细胞死亡途径中的新作用

基本信息

批准号：
9278101
负责人：
Eileen Marie Foy
金额：
$ 19.85万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2018-03-18
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9278101
关键词：
Acute Address Affinity Chromatography Antiviral Agents Apoptosis Aseptic Meningitis Autophagocytosis Award Basic Science Binding Binding Sites Brain Stem Capsid Capsid Proteins Cell Death Cell Death Signaling Process Cells Child Childhood Clathrin Clinical Clinical Sciences Communicable Diseases Complement Complex Core Protein Data Data Set Development Disease Educational workshop Elements Encephalitis Endocytosis Enterovirus Enterovirus 71 Environment Epidemic Epitopes Event Family member Follow-Up Studies Foy Functional disorder Goals Hour Human Human poliovirus Infection Inflammation Inflammatory International Knowledge Life Light Malignant Neoplasms Mass Spectrum Analysis Mediating Medical Medical center Mentors Modeling Modification Mus Mutation Myocarditis Neurologic Symptoms Paralysed Pathogenesis Pathway interactions Pharmacological Treatment Phenotype Physicians Play Post-Translational Protein Processing Process Proteins RNA Regulation Regulatory Pathway Research Research Personnel Research Training Retreatment Role Scientist Series Services Severity of illness Signal Pathway Signal Transduction Specificity Structural Protein TRAF2 gene Texas Therapeutic Time Training Programs Transgenic Mice Translations United States Universities Viral Viral Core Proteins Viral Pathogenesis Viral Physiology Viral Proteins Virion Virus Virus Replication Work base career development clinical development design genetic regulatory protein inhibitor/antagonist insight interest knock-down laboratory experience meetings microbial mimetics mouse model mutant novel pathogen protein complex protein purification public health relevance response scavenger receptor skills small hairpin RNA small molecule stem success therapeutic target tissue culture viral RNA virology

项目摘要

DESCRIPTION (provided by applicant): Dr. Eileen Foy is a pediatric infectious disease physician with an interest in viral pathogenesis that stems from her graduate work in the Medical Scientist Training Program at the University of Texas, Southwestern Medical Center. Her objective in this current project is to combine her clinical and basic science interests in infectius diseases by studying how early events during enterovirus infection modulate the host cell environment to promote a productive infection. EV71 VP4 is a structural protein that forms the inner core of the viral capsid with a well-described role in facilitating viral entry. However, through her preliminary studies, Dr. Foy has shown that VP4 also interacts with important host cellular proteins suggesting that it has critical functions in modulating the intracellular host environment upon entry. Some of these interacting host proteins are involved in the regulation of cell death signaling pathways. Through a series of specific aims, Dr. Foy will examine the role of the EV71 VP4 protein in modulating cell death pathways through its interaction with important regulators of these processes. Initially, she will determine what structural elements in VP4 mediate the interaction with cell death pathway regulatory protein(s) (Aim1). She will then define the role of these host proteins in mediating cell death during enterovirus infection and examine the impact of VP4 on these processes (Aim 2). Finally, she will utilize a murine model of infection to examine the role of the interplay between VP4 and cell death pathways on enterovirus disease pathogenesis (Aim3). The goal of these studies is to understand the novel function(s) of VP4 early during infection in modulating the host environment, specifically regarding cell death pathways and to apply this knowledge to the design of therapeutics targeted to disrupt this critical viral function. This application will also provide the contextual basis for Dr. Foy's ongoing career development to transition to an independent investigator. Her research training will complement her prior laboratory experience and provide her with the technical and intellectual background in viral pathogenesis needed to facilitate independence. A carefully selected committee of internationally recognized scientists and physicians with expertise in virology, microbial pathogenesis, cell death pathways and clinical infectious diseases has been chosen to oversee her progression through this process. Her scientific development will also be enriched through attendance at UCSF courses in pertinent topics, several seminar series, departmental retreats and national and international scientific meetings. Additionally, Dr. Foy will attend career development seminars and workshops offered through UCSF. Lastly, she will support her clinical development through attending on the pediatric infectious diseases service, weekly clinical seminar series and meetings with her clinical mentor. At the end of this award period, Dr. Foy will have developed the necessary skills to launch her own research and clinical agenda as an independent investigator in the field of infectious diseases with a focus on viral pathogenesis.

描述（由适用提供）：Eileen Foy博士是一种儿科感染性疾病物理学，对病毒发病机理感兴趣，她从她在西南医学中心的德克萨斯大学医学科学培训计划中的研究生工作逐步。她在当前项目中的目标是通过研究肠病毒感染期间的早期事件如何调节宿主细胞环境以促进产品感染来结合其感染中的临床和基础科学利益。 EV71 VP4是一种结构蛋白，构成病毒式衣壳的内核，在支撑病毒进入方面具有很好的描述作用。但是，通过她的初步研究，Foy博士表明，VP4还与重要的宿主细胞蛋白相互作用，这表明它在进入时调节细胞内宿主环境方面具有关键功能。这些相互作用的宿主蛋白中的一些参与细胞死亡信号通路的调节。通过一系列特定目标，Foy博士将通过与这些过程的重要调节剂相互作用来检查EV71 VP4蛋白在调节细胞死亡途径中的作用。最初，她将确定VP4中哪些结构元素介导与细胞死亡途径调节蛋白的相互作用（AIM1）。然后，她将定义这些宿主蛋白在肠道病毒感染期间介导细胞死亡中的作用，并检查VP4对这些过程的影响（AIM 2）。最后，她将利用一种鼠类感染模型来检查VP4与细胞死亡途径之间相互作用在肠病毒病发病机理上的作用（AIM3）。这些研究的目的是在调节宿主环境中，特别是关于细胞死亡途径，并将这些知识应用于旨在破坏这种关键病毒功能的治疗剂的设计，以了解感染期间VP4的新功能。该应用程序还将提供上下文 Foy博士正在进行的职业发展的基础，要过渡到独立调查员。她的研究培训将补充她以前的实验室经验，并为她提供促进独立独立性所需的病毒发病机理的技术和智力背景。一项精心挑选的国际认可的科学家和医生委员会在病毒学，微生物发病机理，细胞死亡途径和临床传染病方面具有专业知识，以监督她的进展。她的科学发展也将通过参加相关主题，几个开创性系列，部门务虚会以及国家和国际科学会议的UCSF课程来丰富她的科学发展。此外，Foy博士还将参加UCSF提供的职业发展过程和讲习班。最后，她将通过参加儿科传染病服务，每周临床研讨会系列以及与临床导师的会议来支持她的临床发展。在这个奖项期结束时，Foy博士将开发必要的技能，以作为传染病领域的独立研究者启动自己的研究和临床议程，重点是病毒发病机理。