Identifying Intermolecular Constraints on Influenza Virus Evolution

确定流感病毒进化的分子间限制

• 批准号: 10395814
• 负责人: Jennifer Elizabeth Jones
• 金额: $ 2.79万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2022-11-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395814
• 关键词: Address; Amino Acids; Area; Avian Influenza A Virus; Base Pairing; Biological Assay; Birds; Case Fatality Rates; Communicable Diseases; Complex; Computational Biology; Data; Daughter; Domestic Fowls; Epidemiology; Evolution; Faculty; Foundations; Funding; Genetic; Genomic Segment; Genomics; Goals; Human; Infection; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A virus; Institution; Investigation; Knowledge; Laboratories; Laboratory Research; Lead; Letters; Maps; Measures; Mentors; Mentorship; Messenger RNA; Mission; Molecular; Mutate; National Institute of Allergy and Infectious Disease; Nucleoproteins; Nucleotides; Pathogenicity; Peer Review; Phylogenetic Analysis; Polymerase; Positioning Attribute; Process; Protein Subunits; Public Health; Publications; RNA; Reporter; Research; Role; Site; Site-Directed Mutagenesis; Structure; System; Testing; Training; Trees; Universities; Validation; Viral; Viral Proteins; Virus; Virus Assembly; Zoonoses; aquatic bird; bioinformatics pipeline; career; cross-species transmission; design; global health; influenza virus strain; influenzavirus; innovation; intermolecular interaction; mutant; novel; pandemic disease; prevent; professor; protein complex; protein protein interaction; public health intervention; reverse genetics; success; symposium; viral RNA

PROJECT SUMMARY/ABSTRACT The long-term goals of the candidate are to establish an independent research laboratory investigating host adaptation of zoonotic viruses. This proposal outlines a set of aims that will provide a foundation for a career as a professor at an academic institution. The candidate has established a training plan comprising five main areas: coursework in computational biology, mentorship under a diverse and supportive network of University of Pittsburgh faculty, publication of research in peer-reviewed articles, networking at seminars and conferences, and application for transitional funding and faculty positions. The candidate has assembled a diverse mentoring committee to achieve these goals: Dr. Seema Lakdawala, the primary sponsor; Dr. Vaughn Cooper, co-sponsor of this application; Dr. Erik Wright, collaborator; and a formal mentoring committee including Drs. John Williams, Neal DeLuca, Matthew Nicotra, and Anne-Ruxandra Carvunis. See co-sponsor statement and letters of support. The research objectives proposed in this application include the investigation of the role of complex interactions on influenza virus evolution. Protein-protein interactions determine whether polymerase subunits are compatible, and recently described RNA-RNA interactions are theorized to drive genomic assembly of viral RNA segments into daughter viruses. However, the impact of such complex interactions on viral evolution are not well understood. Such knowledge will ultimately aid in the prediction of how genetic reassortment of genomic segments occurs between two influenza virus strains, a process that leads to emerging pandemic and zoonotic strains. These objectives are in accordance with the mission of the NIAID to better understand and prevent infectious diseases. We hypothesize that evolutionary relationships predict complex interactions among viral RNA and protein that constrain reassortment. We present the following aims to address this hypothesis: Aim 1. To define the mechanism of evolutionary constraints on RNA-RNA interactions in seasonal human IAV. We will identify nucleotide residues underlying our initial observation that parallel evolution occurs between viral RNA and examine their roles in genomic packaging. Aim 2. To examine parallel evolution between protein subunits of avian polymerase complexes. We will test whether complex protein-protein interactions similarly constrain avian influenza virus evolution. These aims will provide a basis for the candidate to launch an independent laboratory distinct from that of her advisor investigating evolutionary constraints on host adaptation of zoonotic viruses. The sponsor, co-sponsor collaborator and mentoring committee are all present at the University of Pittsburgh and can provide the support necessary for this candidate to succeed.

项目摘要/摘要 候选人的长期目标是建立一个独立的研究实验室调查主机 人畜共患病毒的适应。该提案概述了一系列目标，该目标将为职业提供基础 学术机构的教授。候选人制定了一个培训计划，其中包括五个主要领域： 计算生物学的课程，指导下的指导，在多元化和支持的大学网络下 匹兹堡教师，在同行评审文章中的研究发表，在研讨会和会议上进行网络， 以及过渡资金和教师职位的申请。候选人聚集了多样化的指导 实现这些目标的委员会：主要赞助商Seema Lakdawala博士；沃恩·库珀（Vaughn Cooper）博士，共同赞助商 此应用程序；合作者Erik Wright博士；以及包括Drs在内的正式指导委员会。约翰·威廉姆斯， Neal DeLuca，Matthew Nicotra和Anne-Ruxandra Carvunis。请参阅共同发起的声明和支持信。 本应用程序中提出的研究目标包括调查复杂的作用 流感病毒进化的相互作用。蛋白质 - 蛋白质相互作用决定了聚合酶亚基是否是 理论上将兼容且最近描述的RNA-RNA相互作用驱动病毒RNA的基因组组件 细分为女儿病毒。但是，这种复杂相互作用对病毒进化的影响不佳 理解。这些知识最终将有助于预测基因组遗传性的重新分类 段发生在两个流感病毒菌株之间，这一过程导致大流行和人畜共患病 菌株。这些目标符合NIAID的使命，以更好地理解和防止 传染病。我们假设进化关系可以预测 病毒RNA和蛋白质限制了重新分类。我们提出了以下目的旨在解决这一假设： 目标1。定义季节性RNA-RNA相互作用的进化约束机制 人类IAV。我们将确定我们初始观察的基础核苷酸残基 发生在病毒RNA之间，并检查其在基因组包装中的作用。 目标2。检查禽聚合酶复合物的蛋白质亚基之间的平行演化。我们 将测试复杂的蛋白质蛋白相互作用是否类似地限制了禽流感病毒的演变。 这些目标将为候选人提供与她不同的独立实验室的基础 顾问研究了人畜共患病毒宿主适应的进化限制。赞助商，共同发起人 合作者和指导委员会都在匹兹堡大学出席，可以提供支持 这个候选人成功所必需的。