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 该建议描述了一个为期五年的独立研究职业的培训计划 专注于病毒宿主相互作用，决定了小儿大脑感染的敏感性。具体来说， 申请人努力通过改变病毒来阐明病毒遗传变异如何影响神经动力学 功能并诱导免疫逃逸。申请人是一名出席的传染病医师 费城儿童医院（CHOP）接受过基本神经免疫学的博士学位培训。目标 因为这个奖项是发展和完善成功职业所必需的基本技能 独立研究者，包括对大遗传数据进行测序和生物信息学分析的专业知识 组合，病毒基因组编辑以及与病毒感染的体外和体内模型相关的神经学。导师 为此奖项包括Matthew Weitzman博士，他是病毒主持人领域的国际认可领导者 相互作用，以及神经动力学机制的医师科学家丹尼斯·科尔森（Dennis Kolson）博士。添加 申请人的科学职业指导的深度和广度，科学咨询委员会是 由来自不同和互补领域的科学家和医师科学家组成。 Akhtar博士也将 从CHOP和University的University提供的无与伦比的资源和指导中受益 宾夕法尼亚州。 拟议的研究重点是病毒遗传变异性在确定临床表现方面的作用 新生儿疱疹病毒（HSV）疾病的疾病，特别是感染新生儿大脑的能力。 HSV 新生儿大脑的感染会导致严重的脑炎和永久性神经系统缺陷，但这些因素 尚不清楚促进中枢神经系统（CNS）感染。最近的研究表明，大量 HSV基因组内存在遗传变异性，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。成功完成提议的研究将确定 HSV遗传变异与新生儿中枢神经系统疾病有关，确定其对病毒蔓延的影响 神经元及其改变进展到中枢神经系统感染的能力。这将通过大规模病毒来完成 基因组测序以识别最常见与中枢神经系统疾病相关的变异，然后创造 突变病毒的确定鉴定变异对病毒扩散的个人影响 体外腔室测定的简化神经元连接，以及鼠的复杂神经元电路 视网膜。该提案中概述的研究将为新生儿的变化提供首次见解 HSV基因组会影响神经动力毒害和中枢神经系统疾病的发展。