Population Dynamics an Evolutionary Capacity of Viral Quasispecies

种群动态和病毒准种的进化能力

• 批准号: 8505754
• 负责人: Adam Lauring
• 金额: $ 11.42万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2013-08-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8505754
• 关键词: Acquired Immunodeficiency Syndrome; Address; Advisory Committees; Affect; Animal Model; Antiviral Agents; Area; Attenuated Vaccines; Award; Behavior; Biological Assay; Cell Culture Techniques; Clinical; Communicable Diseases; Complex; Complex Mixtures; Computer Simulation; Detection; Development Plans; Disease; Drug resistance; Environment; Equilibrium; Event; Evolution; Exhibits; Failure; Foundations; Future; Genetic; Genetic Determinism; Genetic Variation; Genomics; Goals; Health; Human poliovirus; Immune; Immune response; Individual; Infection; Influenza; Kinetics; Knowledge; Lead; Libraries; Link; Modeling; Mus; Mutagens; Mutation; Nature; Outcome; Pathogenesis; Phenotype; Polioviruses; Population; Population Characteristics; Population Dynamics; Population Genetics; Prevention strategy; Principal Investigator; Process; Property; RNA Viruses; Recovery; Research; Research Personnel; Resources; Role; Shapes; Structure; System; Testing; Time; Training; Vaccines; Variant; Viral; Viral Pathogenesis; Virulence; Virus; Virus Diseases; Work; attenuation; base; career development; experience; fitness; in vivo; in vivo Model; microbial; multidisciplinary; mutant; novel; novel therapeutics; pathogen; population based; pressure; research study; segregation; success; symposium; theories

DESCRIPTION (provided by applicant): This K08 award will provide Dr. Adam Lauring with the necessary resources and protected time to achieve his objective of applying basic aspects of population genetics and quasispecies theory to explain the dynamics of RNA viruses in infected hosts. In so doing, he plans to bridge the gap between contemporary population-based models and clinical infectious diseases. The award will allow Dr. Lauring to accomplish the following career development goals: (1) Gain experience with animal models of infection. (2) Obtain a firm grounding in population genetics and evolutionary theory. (3) Acquire experience with microarray assays and lay a statistical foundation for future genomics studies of complex populations. (4) Develop a working knowledge of computer modeling of evolutionary systems. (5) Become an independent investigator. To achieve these goals, he has developed a comprehensive career development plan that includes didactic coursework, presentation at local and national research conferences, and ongoing input from a multidisciplinary advisory committee of experts in each training area. Because RNA viruses replicate with rapid kinetics and high mutation rates, they exist as a swarm of diverse variants that are genetically linked, interact cooperatively on a functional level, and together contribute to the characteristics of the population. Based on these considerations, virulence is hypothesized to be a population phenotype and determined by the structure, composition, and evolutionary capacity of the infecting population. A novel microarray platform is described, and will be applied to a well-defined in vivo model of infection in two specific aims. (Aim 1) To characterize, at a functional level, the dynamics of an evolving viral population in vivo using poliovirus, an archetypal RNA virus. Experiments are outlined which address the impact of host bottlenecks on viral diversity and the balancing effect of viral mutation rate. (Aim 2) To define evolutionary capacity as a property of the infecting population and its relationship to virulence and attenuation. A library of distinct viral populations will be screened for adaptive potential, and candidates that differ in their evolutionary capacity will be evaluated in pathogenesis and vaccine models. RELEVANCE: RNA viruses cause a wide variety of diseases from AIDS to influenza and are of increasing concern as emerging pathogens and bioterror agents. Their unique evolutionary properties make them particularly challenging targets for vaccines and antiviral drugs. The population-based approach outlined here is broadly applicable to this group of pathogens and may lead to novel therapeutic and preventive strategies.

描述（由申请人提供）：该K08奖将为Adam Lauring博士提供必要的资源和受保护的时间，以实现他的目标，以应用人群遗传学和准特性理论的基本方面，以解释受感染宿主中RNA病毒的动态。这样一来，他计划弥合现代人群模型与临床传染病之间的差距。该奖项将使Lauring博士能够实现以下职业发展目标：（1）获得感染动物模型的经验。 （2）获得人口遗传学和进化论的牢固基础。 （3）获得微阵列分析的经验，并为复杂人群的未来基因组学研究奠定了统计基础。 （4）开发有关进化系统计算机建模的工作知识。 （5）成为独立研究者。为了实现这些目标，他制定了一项全面的职业发展计划，其中包括教学课程，在本地和国家研究会议上的演讲以及每个培训领域的多学科专家咨询委员会的持续投入。由于RNA病毒以快速的动力学和高突变率复制，因此它们存在是遗传上连接的多种变体，在功能水平上进行协同相互作用，并共同有助于人群的特征。基于这些考虑，毒力被认为是人群表型，并取决于感染种群的结构，组成和进化能力。描述了一个新型的微阵列平台，并将应用于两个特定目的的体内感染模型。 （目标1）在功能水平上，使用脊髓灰质炎病毒，一种原型RNA病毒来表征体内不断发展的病毒种群的动力学。概述了实验，以解决宿主瓶颈对病毒多样性和病毒突变率的平衡效应的影响。 （目标2）将进化能力定义为感染人群的特性及其与毒力和衰减的关系。将筛选一个不同病毒群体的文库，以获得自适应潜力，并且在发病机理和疫苗模型中将评估其进化能力不同的候选者。 相关性：RNA病毒引起从艾滋病到流感的各种疾病，并且随着新兴的病原体和生物疾病剂的关注而引起人们的关注。它们独特的进化特性使它们对疫苗和抗病毒药物的靶标特别具有挑战性。此处概述的基于人群的方法广泛适用于这组病原体，并可能导致新颖的治疗和预防策略。