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（由申请人提供）：Eileen Foy 博士是一名儿科传染病医生，对病毒发病机制感兴趣，这源于她在德克萨斯大学西南医学中心医学科学家培训项目中的研究生工作。该项目旨在通过研究肠道病毒感染过程中的早期事件如何调节宿主细胞环境以促进有效感染，将她对传染病的临床和基础科学兴趣结合起来。EV71 VP4 是一种构成肠道病毒内核的结构蛋白。病毒衣壳在促进病毒进入方面具有明确的作用。然而，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，表明它在进入后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参与细胞死亡信号通路的调节，通过一系列具体目标，Foy 博士将研究 EV71 VP4 蛋白通过与这些过程的重要调节因子相互作用而在调节细胞死亡通路中的作用。最初，她将确定 VP4 中的哪些结构元件介导与细胞死亡途径调节蛋白的相互作用（目标 1），然后她将定义这些宿主蛋白在介导肠道病毒感染期间细胞死亡中的作用，并检查 VP4 对这些过程的影响。（目标 2）。最后，她将利用小鼠感染模型来研究 VP4 和细胞死亡途径之间的相互作用对肠道病毒疾病发病机制的作用（目标 3）。 VP4 在感染早期调节宿主环境的功能，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疗法的设计。她的研究培训将补充她之前的实验室经验，并为她提供促进独立所需的病毒发病机制的技术和知识背景。具有病毒学、微生物发病机制、细胞死亡途径和临床传染病专业知识的医生被选中来监督她在这一过程中的进展，她的科学发展也将通过参加加州大学旧金山分校的相关主题课程、多个研讨会系列、部门务虚会和课程而得到丰富。国家和此外，Foy 博士将参加 UCSF 举办的职业发展研讨会和讲习班，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。在此奖励期间，福伊博士将掌握必要的技能，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，重点关注病毒发病机制。