Neurovirulence determinants of neonatal HSV disease

新生儿 HSV 疾病的神经毒力决定因素

• 批准号: 10001052
• 负责人: Lisa Nowoslawski Akhtar
• 金额: $ 19.12万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-18 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001052
• 关键词: Adult; Advisory Committees; Affect; Amino Acids; Antiviral Therapy; Award; Belief; Bioinformatics; Biological Assay; Birth; Body Surface; Brain; CRISPR/Cas technology; Cells; Central Nervous System Diseases; Central Nervous System Infections; Cessation of life; Characteristics; Childhood; Clinical; Collaborations; Communicable Diseases; Complex; Congenital herpes simplex; Data; Data Set; Defect; Development; Development Plans; Disease; Doctor of Philosophy; Encephalitis; Environment; Exhibits; Eye Infections; Foundations; Frequencies; Funding; Generations; Genetic; Genetic Variation; Goals; Growth; Immune; Immunofluorescence Immunologic; In Vitro; Individual; Infant; Infection; Infectious Skin Diseases; International; Measures; Meningoencephalitis; Mentors; Mentorship; Modeling; Morbidity - disease rate; Mus; Mutate; Neonatal; Neuraxis; Neurologic; Neurologic Deficit; Neurons; Optic Nerve; Oral cavity; Pathway interactions; Pediatric Hospitals; Pennsylvania; Phenotype; Philadelphia; Physicians; Population; Predisposition; Proteins; Research; Research Personnel; Research Training; Resources; Retina; Role; Scientist; Simplexvirus; Site; Techniques; Time; Training; Universities; Variant; Viral; Viral Genome; Viral Load result; Viral Physiology; Viral Proteins; Virus; Virus Diseases; Vocational Guidance; anterograde transport; career; genome editing; genome sequencing; human disease; in vivo; in vivo Model; insight; interest; mouse model; mutant; neonatal brain; neonatal infection; neonate; neuroimmunology; neuronal circuitry; neurovirulence; novel strategies; prevent; protein function; retrograde transport; skills; targeted sequencing; tool; viral genomics; virus genetics; virus host interaction; whole genome

Project Summary This proposal describes a five-year training plan for the development of an independent research career focused on the virus-host interactions that dictate susceptibility of the pediatric brain to infection. Specifically, the applicant strives to elucidate how viral genetic variation influences neurovirulence, both by altering viral function and inducing immune escape. The applicant is an attending Infectious Diseases physician at the Children's Hospital of Philadelphia (CHOP) with previous PhD training in basic neuroimmunology. The goals for this award are to develop and refine the essential skills that will be required for a successful career as an independent investigator, including expertise in sequencing and bioinformatic analysis of large genetic data sets, viral genome editing, and neurologically-relevant in vitro and in vivo models of viral infection. The mentors for this award include Dr. Matthew Weitzman, an internationally recognized leader in the field of virus-host interactions, and Dr. Dennis Kolson, a physician-scientist and expert in mechanisms of neurovirulence. To add depth and breadth to the scientific career guidance of the applicant, a scientific advisory committee is composed of scientists and physician-scientists from diverse and complementary fields. Dr. Akhtar will also benefit from the unparalleled resources and mentorship available at both CHOP and the University of Pennsylvania. The proposed research focuses on the role of viral genetic variability in determining the clinical manifestations of neonatal herpes simplex virus (HSV) disease, particularly the ability to infect the neonatal brain. HSV infection of the neonatal brain causes severe encephalitis and permanent neurologic deficits, but the factors that promote central nervous system (CNS) infection are not known. Recent studies show that substantial genetic variability exists within HSV genomes, but have not evaluated how these variations impact viral growth characteristics or human disease manifestations. Successful completion of the studies proposed will identify HSV genetic variations associated with neonatal CNS disease, determine their impact on viral spread between neurons, and their ability to alter progression to CNS infection. This will be accomplished by large-scale viral genomic sequencing to identify variations most frequently associated with CNS disease, followed by creation of mutant viruses to determine the individual impact of identified variations on viral spread between the simplified neuronal connections of in vitro chamber assays, and the complex neuronal circuits of the murine retina. The studies outlined in this proposal will provide the first insights into how variations in the neonatal HSV genome impact neurovirulence and the development of CNS disease.

项目摘要 该建议描述了一个发展独立研究事业的五年培训计划 集中在决定小儿大脑对感染的易感性的病毒-宿主相互作用。具体地说， 申请人致力于阐明病毒遗传变异如何影响神经毒力， 功能和诱导免疫逃逸。申请人是一名传染病主治医生， 费城儿童医院（CHOP），曾接受过基础神经免疫学博士培训。的目标 这个奖项是发展和完善的基本技能，将需要一个成功的职业生涯， 独立调查员，包括大型遗传数据测序和生物信息学分析方面的专业知识 集、病毒基因组编辑和病毒感染的神经学相关的体外和体内模型。导师 该奖项的获奖者包括Matthew Weitzman博士，他是病毒宿主领域的国际公认领导者。 交互作用，以及Dennis Kolson博士，一位物理学家兼科学家和神经毒力机制专家。添加 深度和广度的科学职业指导的申请人，一个科学咨询委员会是 由来自不同和互补领域的科学家和医生科学家组成。阿赫塔尔博士还将 受益于无与伦比的资源和指导，可在CHOP和大学 宾夕法尼亚 拟议的研究重点是病毒遗传变异在确定临床表现中的作用 新生儿单纯疱疹病毒（HSV）疾病，特别是感染新生儿大脑的能力。HSV 新生儿脑感染可引起严重脑炎和永久性神经功能缺损，但这些因素 其促进中枢神经系统（CNS）感染是未知。最近的研究表明， HSV基因组中存在遗传变异，但尚未评估这些变异如何影响病毒生长 特征或人类疾病表现。成功完成拟议的研究将确定 与新生儿CNS疾病相关的HSV遗传变异，确定其对病毒传播的影响 神经元，以及它们改变CNS感染进展的能力。这将通过大规模的病毒 基因组测序，以确定最常见的与CNS疾病相关的变异， 的突变病毒，以确定已确定的变异对病毒传播的个体影响， 简化的神经元连接的体外室测定，和复杂的神经元回路的小鼠 视网膜。本提案中概述的研究将首次深入了解新生儿 HSV基因组影响神经毒力和CNS疾病的发展。