Population Dynamics an Evolutionary Capacity of Viral Quasispecies

描述(申请人提供)：这项K08奖项将为Adam Lauring博士提供必要的资源和保护时间，以实现他的目标，即应用种群遗传学和准种理论的基本方面来解释受感染宿主中的RNA病毒的动态。通过这样做，他计划弥合当代基于人群的模型和临床传染病之间的差距。该奖项将使劳林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)在种群遗传学和进化论方面打下坚实的基础。(3)积累基因芯片分析经验，为今后复杂群体基因组学研究奠定统计学基础。(4)发展进化系统的计算机建模的实用知识。(5)成为独立的调查员。为了实现这些目标，他制定了一项全面的职业发展计划，其中包括授课、在地方和国家研究会议上发表演讲，以及由每个培训领域的专家组成的多学科咨询委员会的持续投入。由于RNA病毒以快速的动力学和高的突变率进行复制，它们作为一群不同的变种存在，这些变种在基因上是相连的，在功能水平上相互作用，并共同对种群的特征做出贡献。基于这些考虑，毒力被假设为一种种群表型，并由感染种群的结构、组成和进化能力决定。描述了一种新的微阵列平台，并将其应用于两个特定目的的明确的体内感染模型。(目标1)在功能水平上描述使用脊髓灰质炎病毒--一种典型的核糖核酸病毒--体内不断演变的病毒种群的动态。概述了解决宿主瓶颈对病毒多样性的影响以及病毒突变率的平衡效应的实验。(目的2)将进化能力定义为感染群体的一种属性及其与毒力和减毒的关系。将对不同病毒种群的库进行适应潜力筛选，并对进化能力不同的候选病毒在发病机制和疫苗模型中进行评估。 相关：RNA病毒导致从艾滋病到流感的多种疾病，并作为新出现的病原体和生物恐怖因子日益受到关注。它们独特的进化特性使它们成为疫苗和抗病毒药物的靶标特别具有挑战性。这里概述的基于人群的方法广泛适用于这类病原体，并可能导致新的治疗和预防策略。

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.