Host Determinants of Tuberculosis Susceptibility

结核病易感性的宿主决定因素

• 批准号: 10219087
• 负责人: CHRISTOPHER M SASSETTI
• 金额: $ 47.7万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-05 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219087
• 关键词: Address; Affect; Alleles; Animal Structures; Animals; Bacteria; CRISPR/Cas technology; Cells; Cobalamin; Complex; Copper; Defect; Disease; Disease Outcome; Disease Progression; Environment; Evaluation; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genotype; Human; Immune; Inbred Mouse; Individual; Infection; KITLG gene; Link; Location; Lysosomes; Methods; Modeling; Mus; Mutant Strains Mice; Mycobacterium tuberculosis; Myeloid Cells; Myelopoiesis; Outcome; Oxidative Stress; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phagosomes; Phenotype; Population; Predisposition; Proto-Oncogene Protein c-kit; Quantitative Trait Loci; Recombinants; Reporter; Resistance; Resources; Role; Severities; Signal Transduction; Sorting - Cell Movement; Stem Cell Factor; Stress; Structure; System; Techniques; Testing; Tuberculosis; Variant; Vesicle; bacterial genetics; cell type; combinatorial; fitness; genetic association; genetic variant; insight; macrophage; mouse genetics; mutant; pathogen; response; structural genomics; trait

Project 1: Host Determinants of TB Susceptility Abstract: The outcomes of Mycobacterium tuberculosis (Mtb) infections are extremely diverse. Many infected individuals show no signs of disease. Among those that do become ill, the timing, location, and severity of pathology are remarkably variable. Genetic diversity in the host population is a major contributor to this variability, but the responsible alleles and mechanisms are poorly defined and have been difficult to address experimentally. In this project, we approach this inherently complex problem by modeling host diversity using a highly genetically diverse, but precisely genetically defined, panel of recombinant inbred mice known as the Collaborative Cross. The unique structure of this population allows the sequential evaluation of variable traits that reflect distinct aspects of pathogenesis. We took advantage of this iterative-phenotyping strategy to dissect the genetic basis of TB susceptibility at multiple levels. These prior studies implicated Kit Ligand (KitL) variation as an important determinant of TB disease in mice and humans, suggested that genetic interactions between pathogen and host are a sensitive metric for detecting new genes that alter disease progression, and highlighted the power of using ex vivo systems to dissect the interaction between Mtb and the macrophage. In the proposed project, we will continue to pursue these strategies to: Aim 1: Investigate the mechanism of KitL-linked susceptibility to TB disease in mice and humans. Aim 2: Use combinatorial mouse and bacterial genetics to dissect host-pathogen genetic interactions. Aim 3: Exploit the CC panel to dissect the Mtb-macrophage interaction. In combination, these new resources and approaches promise to provide fundamentally new insight into the role of host and bacterial genetic variation on the outcome of Mtb infection. !

项目1：结核病易感性的宿主决定因素 摘要：结核分枝杆菌(Mtb)感染的后果是 多种多样。许多感染者没有表现出疾病的迹象。在那些这样做的人中 发病时，病变的时间、位置和严重程度是非常不同的。 寄主种群的遗传多样性是造成这种差异的主要原因，但 负责任的等位基因和机制定义不明确，很难确定 试验性的地址。在这个项目中，我们通过以下方式解决这个本质上复杂的问题 使用高度遗传多样性但精确的遗传建模宿主多样性 确定的，重组近交系小鼠的小组，称为合作杂交。这个 这一群体的独特结构允许对可变性状进行顺序评估 反映了病机的不同方面。我们利用了这种迭代表型分析 从多个层面剖析结核病易感性的遗传基础的策略。这些先例 研究表明Kit Ligand(KitL)变异是结核病的重要决定因素 在小鼠和人类中，表明病原体和宿主之间的遗传相互作用 是检测改变疾病进展的新基因的敏感指标，以及 强调了使用体外系统分析结核分枝杆菌之间相互作用的力量 还有巨噬细胞。在建议的计划中，我们会继续推行这些措施 以下战略： 目的1：探讨KitL连锁对结核病易感性的机制。 老鼠和人类。 目的2：利用组合小鼠和细菌遗传学对宿主病原体进行解剖 基因的相互作用。 目的3：利用CC面板分析结核分枝杆菌与巨噬细胞的相互作用。 这些新的资源和方法结合在一起，有望从根本上提供 宿主和细菌遗传变异对结核分枝杆菌转归的新认识 感染。 好了！