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Host Determinants of Tuberculosis Susceptibility

结核病易感性的宿主决定因素

基本信息

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
项目类别：
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

项目摘要

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：结核敏感性的宿主决定因素