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.

项目概要/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，将为职业生涯奠定基础 学术机构的教授。候选人制定了包括五个主要领域的培训计划： 计算生物学课程，在大学多元化和支持性网络下的指导 匹兹堡教师、发表同行评审文章的研究、在研讨会和会议上建立联系、 以及过渡资金和教职职位的申请。候选人汇集了多元化的指导 委员会实现这些目标： Seema Lakdawala 博士，主要发起人；沃恩·库珀博士，共同发起人 本申请的；埃里克·赖特博士，合作者；和一个正式的指导委员会，包括博士。约翰·威廉姆斯, 尼尔·德卢卡、马修·尼科特拉和安妮-鲁克桑德拉·卡武尼斯。请参阅共同发起人声明和支持信。 本申请提出的研究目标包括调查复杂的作用 流感病毒进化中的相互作用。蛋白质-蛋白质相互作用决定聚合酶亚基是否 兼容的、最近描述的 RNA-RNA 相互作用理论上可以驱动病毒 RNA 的基因组组装 分段成子病毒。然而，这种复杂的相互作用对病毒进化的影响尚不清楚 明白了。这些知识最终将有助于预测基因组的遗传重排如何 片段发生在两种流感病毒株之间，这一过程导致出现大流行和人畜共患病 菌株。这些目标符合 NIAID 的使命，即更好地了解和预防 传染病。我们假设进化关系预测了之间复杂的相互作用 限制重配的病毒RNA和蛋白质。我们提出以下目标来解决这一假设： 目标 1. 定义季节性 RNA-RNA 相互作用的进化限制机制 人类IAV。我们将确定我们最初观察到的平行进化背后的核苷酸残基 发生在病毒 RNA 之间并检查它们在基因组包装中的作用。 目标 2. 检查禽类聚合酶复合物蛋白质亚基之间的平行进化。我们 将测试复杂的蛋白质-蛋白质相互作用是否同样限制禽流感病毒的进化。 这些目标将为候选人建立一个与她的实验室不同的独立实验室提供基础。 顾问研究人畜共患病毒宿主适应的进化限制。发起人、共同发起人 合作者和指导委员会都在匹兹堡大学，可以提供支持 该候选人取得成功所必需的。