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

• 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
• 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

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，具有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不清楚。基因组重排是这种节段RNA病毒遗传变化的主要机制。本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病引入基因，还是现有遗传变异的重组。这个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，其中包括：（1）成为传染病进化方面的专家，结合生物信息学，流行病学建模和基于实验室的进化实验，（2）在领先的医学研究机构中建立独立的医生调查员的职业生涯，（3）成为多个培训机构学员的有效导师。 程度.这些目标将通过一个多元化的导师委员会的指导形式和正式的教学培训相结合来实现，重点是具体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，并将于2016年1月被任命为助理教授。我维持每周半天的门诊和每年一个月的住院服务。我获得了一个博士学位，研究细菌进化的实验进化。在我的奖学金研究期间，我一直由梅赛德斯·帕斯夸尔博士指导，他是传染病生态学和进化理论方面的专家。在她的实验室里，我接受了使用系统发育数据进行进化过程建模的培训。我正在寻求通过将这种进化观点与正式的流行病学建模相结合来增加重要的额外培训，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。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博士和大卫Markovitz博士在实验室病毒学方面的额外培训来实现。此外，我将获得职业指导和专家指导 吉尔伯特·欧门博士的生物信息学分析。工作环境：我的科学目标包括：（1）通过包括流行病学和进化过程来模拟传染病动力学（2）应用贝叶斯系统发育方法来测试生态模型，（3）发展细胞培养中轮状病毒生长，繁殖和操作的实验室技能，以便在实验室进行进化实验。这些科学目标将通过指导和正式粗糙的工作相结合，通过密歇根大学的几个中心，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，计算生物学和医学中心。同样重要的是，我的职业发展目标，其中包括：（1）发展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）的建议，包括负责任的研究行为。(3)提高我的书面和口头沟通技巧。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，以及负责任的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反应中的作用。我计划检验这样的假设，即上位性分子相互作用和人群中的免疫模式都限制了重组病毒在人群中传播的能力，而疫苗接种将改变整个人群的宿主免疫模式，导致重组病毒的传播。目标1将确定历史模式的重配使用贝叶斯系统发育分析两大套全基因组序列。目标2将测量轮状病毒实验室毒株之间的重配率，并利用实验进化绘制可获得的突变途径以应对重配的分子障碍。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的发现如何影响疫苗接种的预期反应。

项目成果

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.

• DOI: 10.1017/ice.2017.279
• 发表时间: 2018-03
• 期刊: Infection control and hospital epidemiology
• 影响因子: 4.5
• 作者: Woods RJ;Patel TS;Nagel JL;Newton DW;Read AF
• 通讯作者: Read AF