PROJECT 1: Identification of host and bacterial pathways that control tuberculosis pathogenesis in humans

项目 1:鉴定控制人类结核病发病机制的宿主和细菌途径

基本信息

  • 批准号:
    10550001
  • 负责人:
  • 金额:
    $ 73.54万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-08-17 至 2028-05-31
  • 项目状态:
    未结题

项目摘要

PROJECT 1: IDENTIFICATION OF HOST AND BACTERIAL PATHWAYS THAT CONTROL TB PATHOGENESIS IN HUMANS SUMMARY Phagocytes of the mammalian innate immune system, in particular macrophages, form the first line of defense upon bacterial infection and are armed with powerful mechanisms to limit bacterial growth and eradicate invaders. In addition to having direct antimicrobial activity, macrophages also initiate and shape powerful inflammatory responses that dramatically influence disease. Bacterial pathogens, however, have evolved mechanisms to thwart these killing mechanisms of phagocytes, and to persist in human tissues. Indeed, the inflammatory pathways robustly elicited by Mycobacterium tuberculosis (Mtb) – the etiological agent of the devastating human disease tuberculosis (TB) and the focus of Project 1 – work to promote bacterial growth and TB disease. However, the host genes and cellular pathways that dictate the outcome of infection are not entirely clear. There is growing evidence that the earliest interactions of Mtb with two very different subsets of lung macrophages, alveolar and “recruited” macrophages, are critical for TB control, but our understanding of the response of alveolar macrophages to Mtb has been limited due to the difficulty in studying these tissue resident lung macrophages. In Project 1, we will use new cellular models of alveolar macrophages coupled with unbiased, systematic approaches to identify the specific molecular networks that underly infection of these different macrophage types. In collaboration with the Technology Core, we will use this information to make predictions about bacterial infectivity that will be tested in human samples and mouse models of infection in an iterative fashion to model host response during infection. These results, and those from Project 2, will be integrated by the Data Management and Bioinformatics and Modeling Cores with existing -omics and human GWAS datasets to identify host and bacterial signatures that correlate significantly with clinical pathogenesis. Importantly, we will focus our functional testing on pathways that are shared between bacterial and viral responses (with Project 2) to understand the mechanisms that lead to synergies during bacterial-viral co-infection.
项目1:确定控制结核病的宿主和生物途径 人类致病机制 总结 哺乳动物先天性免疫系统的吞噬细胞,特别是巨噬细胞,形成了免疫系统的第一线。 防御细菌感染,并配备了强大的机制,以限制细菌生长, 消灭入侵者。除了具有直接的抗微生物活性,巨噬细胞还启动和形成 强大的炎症反应,极大地影响疾病。然而,细菌病原体具有 进化的机制,以阻止这些吞噬细胞的杀伤机制,并坚持在人体组织。 事实上,由结核分枝杆菌(Mtb)强烈引发的炎症途径-病原学 结核病是毁灭性的人类疾病(TB)的病原体,项目1的重点是促进 细菌生长和结核病。然而,决定结果的宿主基因和细胞通路 感染的可能性还不完全清楚。越来越多的证据表明,结核分枝杆菌与两种 非常不同的肺巨噬细胞亚群,肺泡巨噬细胞和“募集”巨噬细胞,对结核病至关重要 对照,但我们对肺泡巨噬细胞对结核分枝杆菌的反应的理解是有限的, 研究这些组织驻留的肺巨噬细胞的困难。在项目1中,我们将使用新的细胞模型, 肺泡巨噬细胞加上公正的,系统的方法,以确定特定的分子 这些网络是这些不同巨噬细胞感染的基础。与技术合作 核心,我们将利用这些信息来预测细菌的感染性,并在人体中进行测试。 样品和小鼠感染模型以迭代方式对感染期间的宿主反应进行建模。 这些结果以及项目2的结果将由数据管理和生物信息学部整合, 使用现有的组学和人类GWAS数据集对核心进行建模,以识别 与临床发病机制密切相关。重要的是,我们将把我们的功能测试集中在通路上, 在细菌和病毒反应之间共享(与项目2),以了解导致 细菌病毒混合感染时的协同作用。

项目成果

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JEFFERY S COX其他文献

JEFFERY S COX的其他文献

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{{ truncateString('JEFFERY S COX', 18)}}的其他基金

UCSF-UCB Tuberculosis Research Advancement Center (TRAC)
UCSF-UCB 结核病研究促进中心 (TRAC)
  • 批准号:
    10431539
  • 财政年份:
    2022
  • 资助金额:
    $ 73.54万
  • 项目类别:
UCSF-UCB Tuberculosis Research Advancement Center (TRAC)
UCSF-UCB 结核病研究促进中心 (TRAC)
  • 批准号:
    10674698
  • 财政年份:
    2022
  • 资助金额:
    $ 73.54万
  • 项目类别:
M. tuberculosis strain-dependent interactions with host cells
结核分枝杆菌与宿主细胞的菌株依赖性相互作用
  • 批准号:
    10459539
  • 财政年份:
    2021
  • 资助金额:
    $ 73.54万
  • 项目类别:
M. tuberculosis strain-dependent interactions with host cells
结核分枝杆菌与宿主细胞的菌株依赖性相互作用
  • 批准号:
    10653910
  • 财政年份:
    2021
  • 资助金额:
    $ 73.54万
  • 项目类别:
Host Pathogen Variation & TB Pathogenesis
宿主病原体变异
  • 批准号:
    10459534
  • 财政年份:
    2021
  • 资助金额:
    $ 73.54万
  • 项目类别:
Host Pathogen Variation & TB Pathogenesis
宿主病原体变异
  • 批准号:
    10271168
  • 财政年份:
    2021
  • 资助金额:
    $ 73.54万
  • 项目类别:
M. tuberculosis strain-dependent interactions with host cells
结核分枝杆菌与宿主细胞的菌株依赖性相互作用
  • 批准号:
    10271172
  • 财政年份:
    2021
  • 资助金额:
    $ 73.54万
  • 项目类别:
Host Pathogen Variation & TB Pathogenesis
宿主病原体变异
  • 批准号:
    10653900
  • 财政年份:
    2021
  • 资助金额:
    $ 73.54万
  • 项目类别:
RESEARCH PROJECT 2
研究项目2
  • 批准号:
    10224018
  • 财政年份:
    2018
  • 资助金额:
    $ 73.54万
  • 项目类别:
Research Training at the Confluence of Infectious and Non-Communicable Diseases in India
印度传染病和非传染性疾病交汇处的研究培训
  • 批准号:
    10361555
  • 财政年份:
    2017
  • 资助金额:
    $ 73.54万
  • 项目类别:

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