Population Genetics of M. Tuberculosis During Disease Epidemics

疾病流行期间结核分枝杆菌的群体遗传学

• 批准号: 7881686
• 负责人: Caitlin S Pepperell
• 金额: $ 11.65万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7881686
• 关键词: Address; American; Archives; Bacteria; Canada; Classification; Clinical; Clinical Data; Collaborations; Communicable Diseases; Communities; Data; Data Set; Daughter; Disease; Epidemic; Epidemiologic Studies; Epidemiology; European; Event; Evolution; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Human; Immune system; Incidence; Life Style; Mentors; Methods; Molecular; Molecular Biology; Morbidity - disease rate; Mutation; Mycobacterium tuberculosis; Native-Born; Organism; Pathogenesis; Pharmaceutical Preparations; Phylogeny; Physicians; Play; Population; Population Genetics; Public Health; Research; Research Personnel; Resources; Restriction Fragment Length Polymorphism Analysis; Role; Saskatchewan; Scientist; Staging; Surveys; Techniques; Time; Training; Tuberculosis; Universities; Vaccines; Variant; age related; authority; base; career development; experience; insight; killings; migration; mycobacterial; pathogen; population genetic structure; population migration; programs; transmission process

DESCRIPTION (provided by applicant): The proposal outlines a 5-year training plan to facilitate Dr. Pepperell's career development as an academic Physician scientist. Dr. Pepperell recently completed clinical training in infectious diseases at Stanford University. The proposed project takes advantage of outstanding technical and intellectual resources available at Stanford for the study of M. tuberculosis. Drs. Gary Schoolnik and Peter Small will serve as co-mentors for the project. Dr. Schoolnik is an internationally recognized authority on the molecular biology and pathogenesis of TB, while Dr. Small has an equally successful research program focused on the evolutionary genetics of M.TB. The candidate proposes to acquire training in bacterial population genetics in order to examine currently unexplained aspects of TB epidemics from the perspective of the pathogen. TB epidemics have historically declined in a stereotypical manner despite variable host populations, treatment and environmental conditions. The hypothesis under study relates the degree of genetic diversity seen within a population of TB organisms to the stage of the disease epidemic in the host population. We hypothesize that genetic diversity increases over time and that biologically important changes in the organism either cause or accompany the natural decline of disease epidemics. Through collaboration with Canadian public health authorities, the candidate has access to a unique dataset which will allow her to examine this hypothesis. Clinical data and archived TB strains are available from 2 well defined populations of Native Canadians which experienced TB epidemics 70 years apart. The candidate proposes to use TB genotyping techniques to create a micro-phylogeny of TB isolates from these communities. The aims are to: 1) reconstruct the evolutionary events which occurred over the course of these epidemics 2) define the strain types which predominate at the initiation versus the conclusion of an epidemic and 3) quantify the amount of diversity generated over the course of an epidemic. The study communities are geographically and socially isolated and there is an opportunity to study the evolution of a small number of TB strains, without the confounding effect of migration. Ultimately, this study should provide insight into the ways in which TB bacteria evolve to avoid attack by the human immune system, drugs and vaccines. An understanding of this evolution would help to develop better treatments for a disease which kills almost 3 million people per year.

描述（由申请人提供）：该提案概述了一个5年的培训计划，以促进Pepperell博士作为学术医师科学家的职业发展。Pepperell博士最近在斯坦福大学完成了传染病的临床培训。该项目利用了斯坦福大学优秀的技术和智力资源来研究结核分枝杆菌。Drs。Gary Schoolnik和Peter Small将担任该项目的联合导师。斯库尔尼克博士是国际公认的结核病分子生物学和发病机制方面的权威，而斯莫尔博士在结核分枝杆菌进化遗传学方面也有同样成功的研究项目。该候选人建议获得细菌种群遗传学方面的培训，以便从病原体的角度研究目前无法解释的结核病流行方面。尽管宿主人口、治疗方法和环境条件各不相同，但结核病流行在历史上以一种典型的方式下降。正在研究的假设将结核生物种群内的遗传多样性程度与宿主种群中疾病流行的阶段联系起来。我们假设遗传多样性随着时间的推移而增加，生物体中重要的生物学变化导致或伴随疾病流行的自然下降。通过与加拿大公共卫生当局的合作，候选人可以访问一个独特的数据集，这将使她能够检验这一假设。临床数据和存档的结核菌株来自相隔70年经历结核病流行的2个定义明确的加拿大土著人群。该候选人建议使用结核基因分型技术创建来自这些社区的结核分离株的微系统发育。其目的是：1)重建在这些流行病过程中发生的进化事件；2)确定在流行病开始和结束时占主导地位的菌株类型；3)量化在流行病过程中产生的多样性数量。这些研究社区在地理上和社会上都是孤立的，因此有机会研究少数结核菌株的演变，而不会受到移民的混杂影响。最终，这项研究应该为结核病细菌如何进化以避免人类免疫系统、药物和疫苗的攻击提供见解。了解这种演变将有助于开发更好的治疗方法，以治疗每年导致近300万人死亡的这种疾病。

项目成果

The role of selection in shaping diversity of natural M. tuberculosis populations.

• DOI: 10.1371/journal.ppat.1003543
• 发表时间: 2013-08
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Pepperell CS;Casto AM;Kitchen A;Granka JM;Cornejo OE;Holmes EC;Birren B;Galagan J;Feldman MW
• 通讯作者: Feldman MW