Systems Genetics of Tuberculosis

结核病的系统遗传学：项目摘要： 结核分枝杆菌(Mtb)的感染结果是高度可变的，创造了一个 结核病控制面临巨大挑战；我们如何识别那些真正处于危险之中的人，以及 提供对该个人有效的干预措施？生物学的 结核分枝杆菌感染结局的决定因素很难确定，主要是因为 涉及多个变量，包括寄主和病原体的遗传变异和 非遗传环境因素。为了克服这种复杂性，我们利用新的 创建哺乳动物和细菌遗传资源的模型系统，可以使用 研究这些变量中的每一个单独和组合的影响。寄主 多样性是使用来自合作十字(CC)的MICE纳入的，CC是一种新的 产生的近交系小鼠的参考板，反映了近交系小鼠的多样性 人口。细菌变异是通过使用大量的结核分枝杆菌菌株组合而成的 既反映了自然产生的多样性，也反映了实验产生的多样性。使用这一高度可驯服的 系统，可以评估受控干预的效果，并具有高分辨率 表型分析可用于区分不同的结核病相关疾病状态。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来： 1)确定结核病易感性的宿主决定因素， 2)确定寄主-病原菌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的效力基础 通过与以鼠标和人类为重点的两个基本科学核心合作 遗传学和一个管理核心，我们将实现我们的终极科学目标： 描述结核病发病的潜在机制，扩展这些 对人类临床队列的观察，并利用这些见解合理地设计更多 有效的疫苗。 好了！

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. !