Population Dynamics an Evolutionary Capacity of Viral Quasispecies

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保护时间，以实现他应用群体遗传学和准种理论的基本方面来解释感染宿主中RNA病毒动态的目标。在这样做的过程中，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)在群体遗传学和进化理论方面获得坚实的基础。(3)获得微阵列分析的经验，为未来复杂人群的基因组学研究奠定统计基础。(4)发展进化系统的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，其中包括教学课程，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病毒以快速动力学和高突变率复制，因此它们作为一群不同的变异体存在，这些变异体在遗传上相互联系，在功能水平上相互作用，并共同促成种群的特征。基于这些考虑，毒力被假设为一种群体表型，并由感染群体的结构、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标的明确定义的体内感染模型。(Aim 1）在功能水平上，使用脊髓灰质炎病毒（一种原型RNA病毒）表征体内进化的病毒群体的动力学。实验概述了解决宿主瓶颈对病毒多样性的影响和病毒突变率的平衡效应。(Aim 2）将进化能力定义为感染种群的一种特性及其与毒力和减毒的关系。将筛选不同病毒群体的文库以获得适应性潜力，并将在发病机制和疫苗模型中评估进化能力不同的候选病毒。 相关性：RNA病毒引起从艾滋病到流感的多种疾病，并且作为新兴病原体和生物恐怖剂越来越受到关注。它们独特的进化特性使它们成为疫苗和抗病毒药物的特别具有挑战性的目标。这里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.