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
基本信息
- 批准号:10271172
- 负责人:
- 金额:$ 45.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-01 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AllelesAnimal ModelBacterial GenesBacterial ProteinsBioinformaticsBiological AssayCBL geneCRISPR/Cas technologyCandidate Disease GeneCell WallCellsClinicalComplementComplexCuesDataData SetDefectDiagnosticDiseaseDisease OutcomeDistalELF3 geneEtiologyFamilyGenesGeneticGenetic VariationGenotypeGoalsGrowthHost resistanceHumanImmuneImmune responseIndividualInfectionInflammatory ResponseInnate Immune ResponseInterferon Type IInterferonsLaboratoriesM. tuberculosis genomeMediatingMessenger RNAModificationMutationMycobacterium tuberculosisNetwork-basedOrganismOutcomePathogenesisPathogenicityPathway interactionsPhagosomesPhenotypePopulationPost-Translational Protein ProcessingPredispositionPrevalenceProteinsProteomicsPulmonary TuberculosisResistanceScanningSiteSystemTechnologyTestingTuberculosisUbiquitinVariantVietnamVirulenceWorkbacterial geneticsbasecausal variantcohortgenetic testinggenome wide association studyhigh resolution imaginghuman pathogenin vivoinnate immune pathwaysinsightmacrophagemouse modelmutantpathogenprogramsrecruitrepairedresponsetranscriptomicstransmission processubiquitin ligase
项目摘要
Tuberculosis (TB) is a multifaceted disease that has extensive variation in clinical manifestations despite being
the product of infection with a single pathogen, Mycobacterium tuberculosis. The extensive genetic diversity in
human and Mycobacterium tuberculosis genomes responsible for differences in clinical outcomes represent
modifications of host-pathogen interactions that are key to pathogenesis. Understanding the basis for these
heterogenous responses will uncover new mechanisms of virulence and resistance and will impact treatment
and diagnostics. Unfortunately, the challenges of studying the mechanisms of differential outcomes of infection
in humans not only includes identification of correlations between host/pathogen genotypes with phenotypes in
human populations, but also the subsequent identification of the mechanisms that are causal for disease which
require studying them in the laboratory without the pathogen’s natural host organism. This Program takes
advantage of unique, ongoing genome-wide association studies (GWAS) that have identified both human and
pathogen variants that are associated with heterogenous clinical responses in two different human populations.
To determine the mechanisms underlying these variations, we will employ a powerful set of experimental
assays, including new proteomics-based scanning platform to probe host responses during experimental
macrophage infection that is orthogonal to traditional mRNA profiling, in order to broadly search for changes in
host innate immune pathways that correlate with disease outcomes associated with these clinical strains.
Based on our preliminary data, we hypothesize that many of these interactions occur early during infection and
are mediated by proteins secreted by M. tuberculosis. In this proposal, we focus primarily on correlations
between two unique sets of clinical bacterial variants, strains that are associated greater transmission of
pulmonary TB disease and strains that are more prone to dissemination to distal sites in the body. An
unexpected theme from both of these sets of strains is the prevalence of TB proteins secreted by the ESX
systems expressed in M. tuberculosis. Both the ESX-1 and ESX-5 secretion systems of M. tuberculosis are
key virulence determinants required for intracellular growth and for eliciting distinct innate immune responses
during macrophage infection. A central hypothesis is that the set of bacterial proteins that influence disease
outcomes are enriched for secreted proteins that mediate interactions between pathogen and host
macrophages. To test this hypothesis, we will collaborate with Cores A and B to use an integrative approach
to combine genetic data from the M. tuberculosis GWAS datasets with genetic and proteomic screen to identify
causal genes that mediate interactions with macrophages. We will use these same technologies to collaborate
with Projects 2 and 3 to identify proteins/pathways responsible for host resistance and bacterial
dissemination.
结核病是一种多方面的疾病,其临床表现具有广泛的多样性。
结核分枝杆菌感染一种单一病原体的产物。中国丰富的遗传多样性
导致临床结果差异的人类和结核分枝杆菌基因组代表
宿主-病原体相互作用的修饰是发病机制的关键。了解这些问题的基础
异质性反应将揭示毒力和耐药性的新机制,并将影响治疗
和诊断学。不幸的是,研究感染不同结局的机制面临的挑战
在人类中,不仅包括鉴定宿主/病原体基因类型与表型之间的相关性
以及随后对引起疾病的机制的识别,这些疾病
要求在没有病原体自然寄主的情况下在实验室进行研究。此计划需要
独特的、正在进行的全基因组关联研究(GWAS)的优势,这些研究已经确定了人类和
在两个不同的人群中与不同的临床反应相关的病原体变异。
为了确定这些变异背后的机制,我们将采用一套强大的实验
检测,包括新的基于蛋白质组学的扫描平台,用于探测实验期间的宿主反应
巨噬细胞感染,与传统的信使核糖核酸图谱垂直,以便广泛地寻找
宿主与这些临床菌株相关的疾病结局的先天免疫途径。
根据我们的初步数据,我们假设其中许多相互作用发生在感染和感染的早期
是由结核分枝杆菌分泌的蛋白质介导的。在本提案中,我们主要关注相关性
在两组独特的临床细菌变异之间,与更大程度上传播
肺结核病和更容易扩散到身体远端部位的菌株。一个
这两组菌株出人意料的主题是ESX分泌的结核蛋白的流行
用结核分枝杆菌表达的系统。结核分枝杆菌的ESX-1和ESX-5分泌系统都是
细胞内生长和激发不同的天然免疫反应所需的关键毒力决定因素
在巨噬细胞感染期间。一个中心假设是影响疾病的一组细菌蛋白质
结果丰富了介导病原菌和宿主之间相互作用的分泌蛋白
巨噬细胞。为了验证这一假设,我们将与内核A和内核B合作,使用一种综合方法
将来自结核分枝杆菌Gwas数据集的遗传数据与遗传和蛋白质组筛选相结合以鉴定
调节与巨噬细胞相互作用的因果基因。我们将使用这些相同的技术进行协作
项目2和项目3确定与宿主抗性和细菌有关的蛋白质/途径
传播。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
JEFFERY S COX其他文献
JEFFERY S COX的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
$ 45.08万 - 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:
$ 45.08万 - 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:
$ 45.08万 - 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:
$ 45.08万 - 项目类别:
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
- 批准号:
10550001 - 财政年份:2018
- 资助金额:
$ 45.08万 - 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:
$ 45.08万 - 项目类别:
相似海外基金
Quantification of Neurovasculature Changes in a Post-Hemorrhagic Stroke Animal-Model
出血性中风后动物模型中神经血管变化的量化
- 批准号:
495434 - 财政年份:2023
- 资助金额:
$ 45.08万 - 项目类别:
Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development
评价唇裂修复疤痕对颅面生长发育影响的小动物模型
- 批准号:
10642519 - 财政年份:2023
- 资助金额:
$ 45.08万 - 项目类别:
Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model
用于大型动物模型半月板损伤修复的生物活性可注射细胞支架
- 批准号:
10586596 - 财政年份:2023
- 资助金额:
$ 45.08万 - 项目类别:
A Comparison of Treatment Strategies for Recovery of Swallow and Swallow-Respiratory Coupling Following a Prolonged Liquid Diet in a Young Animal Model
幼年动物模型中长期流质饮食后吞咽恢复和吞咽呼吸耦合治疗策略的比较
- 批准号:
10590479 - 财政年份:2023
- 资助金额:
$ 45.08万 - 项目类别:
Diurnal grass rats as a novel animal model of seasonal affective disorder
昼夜草鼠作为季节性情感障碍的新型动物模型
- 批准号:
23K06011 - 财政年份:2023
- 资助金额:
$ 45.08万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model
自然发生的青光眼动物模型的纵向眼部变化
- 批准号:
10682117 - 财政年份:2023
- 资助金额:
$ 45.08万 - 项目类别:
A whole animal model for investigation of ingested nanoplastic mixtures and effects on genomic integrity and health
用于研究摄入的纳米塑料混合物及其对基因组完整性和健康影响的整体动物模型
- 批准号:
10708517 - 财政年份:2023
- 资助金额:
$ 45.08万 - 项目类别:
A Novel Large Animal Model for Studying the Developmental Potential and Function of LGR5 Stem Cells in Vivo and in Vitro
用于研究 LGR5 干细胞体内外发育潜力和功能的新型大型动物模型
- 批准号:
10575566 - 财政年份:2023
- 资助金额:
$ 45.08万 - 项目类别:
Elucidating the pathogenesis of a novel animal model mimicking chronic entrapment neuropathy
阐明模拟慢性卡压性神经病的新型动物模型的发病机制
- 批准号:
23K15696 - 财政年份:2023
- 资助金额:
$ 45.08万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
The effect of anti-oxidant on swallowing function in an animal model of dysphagia
抗氧化剂对吞咽困难动物模型吞咽功能的影响
- 批准号:
23K15867 - 财政年份:2023
- 资助金额:
$ 45.08万 - 项目类别:
Grant-in-Aid for Early-Career Scientists