Population Dynamics an Evolutionary Capacity of Viral Quasispecies

描述（由申请人提供）：这个K08奖将为亚当·劳林博士提供必要的资源和保护时间，以实现他的目标，即应用群体遗传学和准物种理论的基本方面来解释RNA病毒在受感染宿主中的动态。通过这样做，他计划弥合当代基于人口的模型与临床传染病之间的差距。该奖项将使劳林博士实现以下职业发展目标：(1)获得感染动物模型的经验。(2)在群体遗传学和进化理论方面有扎实的基础。(3)积累微阵列分析经验，为未来复杂群体基因组学研究奠定统计学基础。(4)发展进化系统计算机建模的工作知识。(5)成为独立调查员。为了实现这些目标，他制定了一个全面的职业发展计划，包括教学课程，在地方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病毒具有快速的复制动力学和高突变率，它们以一群不同的变体的形式存在，这些变体在基因上是相互联系的，在功能水平上相互作用，共同促进了群体的特征。基于这些考虑，毒力被假设为一种种群表型，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，并将在两个特定目标中应用于定义良好的体内感染模型。（目标1）在功能水平上，利用脊髓灰质炎病毒（一种原型RNA病毒）在体内进化的病毒种群的动力学特征。本文概述了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。（目标2）将进化能力定义为感染种群的特性及其与毒力和衰减的关系。将筛选不同病毒种群的适应潜力，并在其进化能力方面存在差异的候选病毒将在发病机制和疫苗模型中进行评估。

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.