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

• 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
• 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

 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的研究生工作。她在这个项目中的目标是联合收割机通过研究肠道病毒感染早期事件如何调节宿主细胞环境以促进生产性感染，结合她对感染性疾病的临床和基础科学兴趣。EV71 VP4是一种结构蛋白，形成病毒衣壳的内核，在促进病毒进入方面具有充分描述的作用。然而，通过她的初步研究，Foy博士已经表明，VP4也与重要的宿主细胞蛋白相互作用，这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质中的一些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EV 71 VP 4蛋白通过与这些过程的重要调节因子的相互作用在调节细胞死亡途径中的作用。首先，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（Aim1）的相互作用。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的作用，并研究VP4对这些过程的影响（目的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（Aim3）。这些研究的目的是了解VP4在感染早期调节宿主环境的新功能，特别是关于细胞死亡途径，并将这些知识应用于靶向破坏这种关键病毒功能的治疗方法的设计。此应用程序还将提供上下文 Foy博士的持续职业发展的基础上过渡到一个独立的调查员。她的研究培训将补充她以前的实验室经验，并为她提供必要的技术和知识背景，以促进独立性的病毒发病机制。一个精心挑选的国际公认的科学家和医生在病毒学，微生物发病机制，细胞死亡途径和临床传染病的专业知识委员会已被选中，以监督她通过这一过程的进展。她的科学发展也将通过参加UCSF课程的相关主题，几个系列研讨会，部门务虚会和国家和国际科学会议丰富。此外，福伊博士将参加通过UCSF提供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和与她的临床导师会议来支持她的临床发展。在这个奖项结束时，福伊博士将开发必要的技能，推出她自己的研究和临床议程作为一个独立的研究人员在传染病领域的重点是病毒的发病机制。