Identifying Intermolecular Constraints on Influenza Virus Evolution

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，调查东道主 人畜共患病毒的适应。这份提案勾勒出了一系列目标，这些目标将为职业生涯奠定基础 学术机构的教授。候选人已经制定了一项包括五个主要领域的培训计划： 计算生物学的课程工作，在多种多样的支持网络下的导师 匹兹堡教师，发表同行评议文章中的研究，在研讨会和会议上建立联系， 申请过渡性基金和教员职位。这位候选人已经组织了一系列不同的指导 实现这些目标的委员会：Seema Lakdawala博士，主要赞助人；Vaughn Cooper博士，共同赞助人 本申请的合作者埃里克·赖特博士，以及包括约翰·威廉姆斯博士在内的正式指导委员会， 尼尔·德卢卡、马修·尼科特拉和安妮-鲁珊德拉·卡武尼斯。见共同赞助者声明和支持函。 在本申请中提出的研究目标包括研究复合体的作用 流感病毒进化的相互作用。蛋白质-蛋白质相互作用决定聚合酶亚基是否 相容的和最近描述的RNA-RNA相互作用被理论上驱动病毒RNA的基因组组装 分割成子代病毒。然而，这种复杂的相互作用对病毒进化的影响并不是很好。 明白了。这些知识最终将有助于预测基因组的遗传重组 片段出现在两种流感病毒株之间，这一过程导致了新的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示着复杂的相互作用 限制重组的病毒RNA和蛋白质。为了解决这一假设，我们提出了以下目标： 目的1.明确进化对季节性RNA-RNA相互作用的制约机制 人体IAV。我们将确定我们最初观察到的并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。 目的2.研究禽类聚合酶复合体蛋白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类似地限制禽流感病毒的进化。 这些目标将为候选人建立一个有别于她的独立实验室提供基础 研究人畜共患病毒宿主适应的进化制约因素的顾问。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 对这位候选人的成功来说是必要的。

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.