Systems Genetics of Tuberculosis

结核病的系统遗传学：项目摘要： 结核分枝杆菌（Mtb）感染的结果是高度可变的， 结核病控制的巨大挑战;我们如何识别那些真正处于风险中的人， 提供一种对该个体有效的干预措施？生物 结核分枝杆菌感染结果的决定因素很难确定，主要是因为 涉及多个变量，包括宿主和病原体的遗传变异， 非遗传环境因素。为了克服这种复杂性，我们利用了新的 哺乳动物和细菌遗传资源，以创建一个模型系统， 来研究这些变量中的每一个单独或组合的影响。主机 使用来自“协作交叉”（CC）的小鼠， 产生的近交系小鼠的参考组，其反映远交系小鼠的多样性。 人口使用大量的Mtb菌株组合来合并细菌变异， 反映了自然和实验产生的多样性。利用这个高度易处理的 系统，可以评估受控干预的效果，并且高分辨率 表型分析可用于区分不同的TB相关疾病状态。三 相互关联的科学项目将使用这一独特的易于处理的实验系统： 1)定义结核病易感性的宿主决定因素， 2)确定宿主-病原体偏好的细菌决定因素。 3)研究结核病疫苗在遗传多样性人群中有效性的基础 通过与专注于小鼠和人类的两个重要科学核心的合作， 遗传学和一个行政核心，我们将实现我们的最终科学目标： 结核病发病机制的特点，扩展这些 观察人类临床队列，并使用这些见解合理设计更多 有效的疫苗。 !

Systems Genetics of Tuberculosis: Program Abstract: Mycobacterium tuberculosis (Mtb) infection outcomes are highly variable, creating a great challenge in TB control; how do we identify those that are genuinely at risk and deliver an intervention that will be effective for that individual? The biological determinants of Mtb infection outcome have been difficult to define largely because multiple variables are involved, which include genetic variation in host and pathogen and non-genetic environmental factors. To overcome this complexity, we leveraged new mammalian and bacterial genetic resources to create a model system that can be used to study the effect of each of these variables in isolation and in combination. Host diversity is incorporated using mice from the “Collaborative Cross” (CC), a newly generated reference panel of inbred mice that reflects the diversity of an outbred population. Bacterial variation is incorporated using large panels of Mtb strains that reflect both naturally- and experimentally-generated diversity. Using this highly-tractable system, the effect of controlled interventions can be assessed, and high-resolution phenotyping can be applied to differentiate different TB-related disease states. Three inter-related scientific projects will use this uniquely tractable experimental system to: 1) Define host determinants of TB susceptibility, 2) Identify bacterial determinants of host-pathogen preference. 3) Investigate the basis for TB vaccine efficacy in genetically-diverse populations Through collaboration with two essential Scientific Cores focused on Mouse and Human genetics and one Administrative Core, we will accomplish our ultimate scientific goals: to characterize the mechanisms underlying tuberculosis pathogenesis, extend these observations to human clinical cohorts, and use these insights to rationally-design more effective vaccines. !