Population Dynamics of Rotavirus: A Combined Theoretical, Bioinformatic and Laboratory Based Approach

描述(申请人提供)：轮状病毒是全球儿童死亡的主要原因，表现出广泛的遗传多样性和复杂的流行病学动态。对最近引进的疫苗的短期或长期进化反应的可能性还没有得到很好的了解。基因组重组是这种节段式RNA病毒基因改变的主要机制。这项提案中的研究将评估重组作为一种潜在的逃避疫苗接种压力的模式的作用，无论是通过人畜共患病的基因引入，还是通过重新洗牌现有的基因变异。这一奖项将在帮助我实现我的长期职业目标方面发挥关键作用，这些目标包括：(1)成为传染病进化方面的专家，结合生物信息学、流行病学建模和基于实验室的进化实验；(2)在一家领先的医学研究机构建立独立内科研究员的职业生涯；(3)成为多所大学学员的有效导师 级别。这些目标将通过由不同导师委员会组成的指导和专注于具体职业和科学发展目标的正式教学培训相结合来实现。候选人：我目前是密歇根大学传染病系的临床讲师，将于2016年1月被任命为助理教授。我有一个门诊，每周半天，每年住院一个月。我获得了利用实验进化论研究细菌进化的博士学位。在我的研究员研究期间，我得到了梅赛德斯·帕斯夸尔博士的指导，他是传染病生态学和进化论理论方面的专家。在她的实验室里，我接受了使用系统发育数据对进化过程进行建模的培训。我正在寻求通过将这种进化论观点与正式的流行病学建模相结合，以及开发基于实验室的实验进化系统来进一步测试我们的假设，从而增加重要的额外培训。这将通过帕斯夸尔博士的持续指导以及与病毒学和病毒进化专家亚当·劳林博士和大卫·马科维茨博士在实验室病毒学方面的额外培训来实现。此外，我还将得到职业指导和专家指导 在吉尔伯特·奥曼博士的生物信息学分析中。环境：我的科学目标包括：(1)通过包含流行病学和进化过程来对传染病动力学进行建模；(2)应用贝叶斯系统发育方法来测试生态模型；(3)开发轮状病毒在细胞培养中的生长、繁殖和操纵方面的实验室技能，以便在实验室进行进化实验。这些科学目标将通过密歇根大学的几个中心通过指导和正式的粗略工作相结合来实现，这些中心包括密歇根临床与健康研究所、统计咨询和研究中心以及复杂系统中心、计算生物学和医学中心。同样重要的是，我的职业发展目标包括：(1)培养管理跨学科项目的领导技能。(2)写作 有效的机构审查委员会(IRB)建议，包括负责任的研究行为。(3)提高我的书面和口头沟通能力。具体的教学计划和课程将被利用，包括密歇根临床和健康研究所，IRBMED，以及负责研究和奖学金的教育和评估计划。研究：拟议研究的目标是确定重组在轮状病毒对疫苗接种的反应中的作用。我计划测试这一假设，即上位性分子相互作用和人类群体之间的免疫模式都限制了重组病毒在人群中传播的能力，并且疫苗接种将改变整个群体的宿主免疫模式，导致重组病毒的传播。目标1将通过对两组大的全基因组序列进行贝叶斯系统发育分析，确定重新排序的历史模式。目的2将测量轮状病毒实验室毒株之间的重组率，并利用实验进化绘制可访问的突变路径，以响应重配的分子障碍。目标3将使用轮状病毒动力学的模拟模型，该模型整合了进化和流行病学动力学，以探索目标1和目标2的发现如何影响对疫苗接种的预期反应。

DESCRIPTION (provided by applicant): Rotavirus, a leading cause of childhood death globally, exhibits extensive genetic diversity and complex epidemiological dynamics. The possibility of short-term or long-term evolutionary response to the recently introduced vaccines is not well understood. Genome reassortment is the major mechanisms of genetic change in this segmented RNA virus. The research in this proposal will evaluate the role of reassortment as a potential mode of escape from vaccination pressure, either through zoonotic introduction of genes, or reshuffling of existing genetic variation. This award will play a critical role in helpin me achieve my long-term career goals, which include: (1) becoming and expert in the evolution of infectious diseases, combining bioinformatics, epidemiological modeling, and laboratory based evolution experiments, (2) establishing a career as an independent physician investigator in a leading medical research institution, (3) becoming an effective mentor to trainees at multiple levels. The goals will be achieved through a combination of a mentoring form a diverse mentorship committee, and formal didactic training, focusing on specific career and scientific development goals. Candidate: I am currently a Clinical Lecturer in the Division of Infectious Diseases at the University of Michigan, and will be appointed Assistant Professor in Jan 2016. I maintain an outpatient clinic of one half day a week and one month of inpatient service per year. I received a PhD studying bacterial evolution using experimental evolution. During my fellowship research period, I have been mentored by Dr. Mercedes Pascual, an expert in the theoretical aspects of infectious disease ecology and evolution. In her lab I received training in the use of modeling of evolutionary processes using phylogenetic data. I am seeking to add significant additional training by combining this evolutionary perspective with formal epidemiological modeling, as well as developing laboratory based experimental evolution system to further test our hypotheses. This will be achieved by through continued mentorship by Dr. Pascual with additional training in laboratory virology with Dr. Adam Lauring and Dr. David Markovitz, experts in virology and viral evolution. Additionally, I will receive career guidance and expert mentorship in bioinformatics analyses by Dr. Gilbert Omenn. Environment: My scientific goals include: (1) modeling of infectious disease dynamics by including both epidemiological and evolutionary processes (2) applying Bayesian phylogenetic methods to test ecological models, (3) Developing laboratory skills in the growth, propagation and manipulation of rotavirus in cell culture in order to carry out evolution experiments in the lab. These scientific goals will be achieved by a combination of mentoring and formal coarse work through several centers at the University of Michigan including the Michigan Institute for Clinical & Health Research, Center for Statistical Consultation and Research, and the Center for Complex systems, Center for Computational Biology and Medicine. Of equal importance, my career development goals, which include: (1) Develop leadership skills for managing an interdisciplinary project. (2) Writing effective institutional review board (IRB) proposals, including the responsible conduct of research. (3) Improve my written and oral communication skills. Specific instructional programs and courses will be utilized including the Michigan Institute for Clinical and Health Research, IRBMED, and the Program for Education and Evaluation in Responsible Research and Scholarship. Research: The goal of the proposed research is to identify the role of reassortment in the response of rotavirus to vaccination. I plan to test the hypothesis that both epistatic molecular interactions and the patterns of immunity among the human population limit the ability of reassorted viruses to spread in the population, and that vaccination will change the population-wide patterns of host immunity, resulting in spread of reassortant viruses. Aim 1 will identify historical patterns of reassortment using a Bayesian phylogenetic analysis of two large sets of whole genome sequences. Aim 2 will measure reassortment rates between laboratory strains of rotavirus, and map accessible mutational pathway to respond to the molecular barriers to reassortment using experimental evolution. Aim 3 will use a simulation model of rotavirus dynamics that integrates the evolutionary and epidemiological dynamics to explore how the findings form Aim 1 and Aim 2 affect the expected response to vaccination.