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

轮状病毒的种群动态：理论、生物信息学和实验室相结合的方法

基本信息

批准号：
9905480
负责人：
Robert J Woods
金额：
$ 19.52万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9905480
关键词：
Address Affect Alleles Ambulatory Care Facilities Animals Award Binding Bioinformatics Biology Cell Culture System Cell Culture Techniques Cessation of life Childhood Clinical Communicable Diseases Complex Computational Biology Conflict (Psychology)Consultations Country County Data Data Set Developed Countries Developing Countries Development Diarrhea Doctor of Philosophy Ecology Environment Epidemiology Event Evolution Exhibits Fellowship Frequencies Gene Combinations Genes Genetic Genetic Variation Genome Goals Growth Health Human Immune Immunity Institutes Institution Institutional Review Boards Instruction Laboratories Lead Leadership Location Maps Measures Medical Research Medicine Mentors Mentorship Methods Michigan Modeling Molecular Molecular Biology Monitor Mutation Pathway interactions Pattern Phylogenetic Analysis Physicians Placebos Play Population Population Dynamics Positioning Attribute Process Proteins Public Health RNA Viruses Reassortant Viruses Research Research Personnel Resistance Role Rotavirus Scholarship System Testing Time Training Universities Vaccination Vaccines Viral Virus Vocational Guidance Work World Health Organization Writing Zoonoses base career career development education evaluation epidemiological model experimental study fitness improved infectious disease evolution infectious disease model inpatient service lecturer mathematical model models and simulation novel novel vaccines oral communication pathogen preservation pressure professor programs public health relevance response responsible research conduct skills statistical center surveillance data transmission process vaccine effectiveness vaccine trial vaccine-induced immunity virology whole genome

项目摘要

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.

描述（由申请人提供）：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。最近推出的疫苗产生短期或长期进化反应的可能性尚不清楚。基因组重排是这种分段 RNA 病毒遗传变化的主要机制。该提案中的研究将评估重配作为逃避疫苗接种压力的潜在模式的作用，无论是通过人畜共患基因的引入，还是现有遗传变异的重新洗牌。该奖项将在帮助我实现长期职业目标方面发挥关键作用，其中包括：（1）成为传染病进化方面的专家，结合生物信息学、流行病学模型和基于实验室的进化实验，（2）建立在领先的医学研究机构担任独立医师研究员的职业生涯，(3) 成为多个机构实习生的有效导师水平。这些目标将通过多元化指导委员会的指导和正式的教学培训相结合来实现，重点关注特定的职业和科学发展目标。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。我每周维持一个半天的门诊，每年一个月的住院服务。我获得了利用实验进化研究细菌进化的博士学位。在我的奖学金研究期间，我得到了传染病生态学和进化理论方面的专家 Mercedes Pascual 博士的指导。在她的实验室中，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观点与正式的流行病学模型相结合，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来增加重要的额外培训。这将通过 Pascual 博士的持续指导以及病毒学和病毒进化专家 Adam Lauring 博士和 David Markovitz 博士在实验室病毒学方面的额外培训来实现。此外，我还将获得职业指导和专家指导 Gilbert Omenn 博士的生物信息学分析。环境：我的科学目标包括：（1）通过流行病学和进化过程对传染病动态进行建模（2）应用贝叶斯系统发育方法来测试生态模型，（3）发展轮状病毒生长、传播和操作的实验室技能细胞培养，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多个中心的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、复杂系统中心、计算中心生物学和医学。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) 提案，包括负责任的研究行为。（3）提高我的书面和口头沟通能力。将利用具体的教学计划和课程，包括密歇根临床与健康研究所、IRBMED 以及负责任研究和奖学金教育和评估计划。研究：拟议研究的目标是确定重配在轮状病毒对疫苗接种反应中的作用。我计划检验这样的假设：上位分子相互作用和人群中的免疫模式都限制了重配病毒在人群中传播的能力，并且疫苗接种将改变人群范围内的宿主免疫模式，从而导致病毒的传播。重配病毒。目标 1 将使用两组全基因组序列的贝叶斯系统发育分析来识别重配的历史模式。目标 2 将测量轮状病毒实验室毒株之间的重配率，并绘制可访问的突变途径，以利用实验进化应对重配的分子障碍。目标 3 将使用轮状病毒动力学模拟模型，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 的研究结果如何影响对疫苗接种的预期反应。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

An orally administered drug prevents selection for antibiotic-resistant bacteria in the gut during daptomycin therapy.

DOI：
10.1093/emph/eoac035
发表时间：
2022
期刊：
EVOLUTION MEDICINE AND PUBLIC HEALTH
影响因子：
3.7
作者：
Morley, Valerie J.;Sim, Derek G.;Penkevich, Aline;Woods, Robert J.;Read, Andrew F.
通讯作者：
Read, Andrew F.

An adjunctive therapy administered with an antibiotic prevents enrichment of antibiotic-resistant clones of a colonizing opportunistic pathogen.

DOI：
10.7554/elife.58147
发表时间：
2020-12-01
期刊：
eLife
影响因子：
7.7
作者：
Morley VJ;Kinnear CL;Sim DG;Olson SN;Jackson LM;Hansen E;Usher GA;Showalter SA;Pai MP;Woods RJ;Read AF
通讯作者：
Read AF

Institution-wide and Within-Patient Evolution of Daptomycin Susceptibility in Vancomycin-Resistant Enterococcus faecium Bloodstream Infections.