Population Genetics of M. Tuberculosis During Disease Epidemics

描述(由申请者提供)：该提案概述了一项为期5年的培训计划，以促进佩佩雷尔博士作为一名学术内科科学家的职业发展。佩佩雷尔博士最近在斯坦福大学完成了传染病临床培训。拟议的项目利用了斯坦福大学现有的优秀技术和智力资源，用于研究结核分枝杆菌。加里·斯库尔尼克博士和彼得·斯莫尔博士将担任该项目的共同导师。斯科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，而斯莫尔博士也有一个同样成功的研究项目，专注于结核分枝杆菌的进化遗传学。候选人建议接受细菌群体遗传学方面的培训，以便从病原体的角度检查目前尚未解释的结核病流行方面。尽管宿主人口、治疗和环境条件各不相同，但结核病流行历来以一种刻板印象的方式下降。正在研究的假说将结核病生物种群中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变化要么导致疾病流行的自然下降，要么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，候选人可以获得一个独特的数据集，这将使她能够检验这一假设。临床数据和已存档的结核病菌株可从两个定义明确的加拿大土著人口中获得，他们相隔70年经历了结核病流行。候选人建议使用结核病基因分型技术来创建来自这些社区的结核病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)确定在疫情开始与结束时占主导地位的菌株类型；3)量化在疫情过程中产生的多样性的数量。研究社区在地理和社会上是孤立的，有机会研究少量结核病菌株的进化，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进化以避免人类免疫系统、药物和疫苗的攻击提供洞察力。对这一演变的了解将有助于为这种每年导致近300万人死亡的疾病开发更好的治疗方法。

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.