Tracking the dynamics of the macrophage response to interferon-gamma at a single-cell level
在单细胞水平追踪巨噬细胞对干扰素γ反应的动态
基本信息
- 批准号:10388046
- 负责人:
- 金额:$ 3.97万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:BacteriaBiological AssayBiological ModelsCell LineCellsChromatinCommunicable DiseasesComplexDataDifferential EquationDiseaseEP300 geneEngineeringEnvironmentFoundationsGBP1 geneGene ExpressionGene Expression ProfileGenesGenetic EngineeringHeterogeneityHost DefenseHumanIRF1 geneImageImmuneImmune responseIndividualInfectionInfection ControlInflammatoryInflammatory ResponseInterferon Type IIKineticsMediatingMicrobeMicrofluidic MicrochipsMicrofluidicsModelingMycobacterium tuberculosisNOS2A geneNitric Oxide SynthaseOutcomePatientsPatternPhysiologic pulsePlayPopulationRegulationReporterReporter GenesRoleSamplingSignal TransductionSourceStimulusSymptomsSystemTestingTimeTissuesTuberculosisWorkadaptive immune responsecell typechromatin remodelingcytokinecytotoxicexperienceexperimental studygenetic variantglobal healthimmunopathologyimprovedin vivoinhibitorinsightlive cell imagingmacrophagemathematical modelnetwork architecturenew therapeutic targetnovelpredicting responsepredictive modelingpromoterresponsetranscription factor USF
项目摘要
Project Summary
Precise temporal regulation of inflammatory responses is required to clear infection without damaging healthy
tissue. Previous work elucidating the mechanisms involved in this regulation have focused mainly on single
time points or bulk samples of cells. However, immune cells in vivo receive complex temporal combinations of
stimuli during an immune response, respond with gene expression patterns that vary over time, and display
heterogeneity within the population. Interferon gamma (IFNγ) is a pro-inflammatory cytokine that plays key
roles in immune responses. Macrophages are immune cells that are one of the primary responders to IFNγ.
During infection, macrophages may experience multiple periods of IFNγ stimulation, and employ signaling and
gene expression networks to decode these varying stimuli into gene expression responses and diverse
functions. GBP1 and NOS2 are two IFNγ-responsive genes that have important roles in host defense against
microbes and are regulated by different network architectures and chromatin regulatory mechanisms.
Mycobacterium tuberculosis (Mtb) infection is a pressing global health issue that also depends critically on
macrophage responses to IFNγ. Mtb infection outcomes are heterogeneous on the cellular as well as the
organismal (human) level. Previous work has shown that IFNγ signaling is essential for macrophages to kill
intracellular Mtb and that this ability to kill Mtb varies between cells. This proposal uses a system that
combines endogenous fluorescent gene reporters in macrophage cell lines with long-term live-cell imaging in a
microfluidic device to simultaneously track expression kinetics of multiple genes in response to dynamic
stimuli, as well as the outcomes of Mtb infection, in the same single cells over time. This can be used to obtain
a quantitative understanding of the mechanisms underlying kinetic gene expression responses and functional
heterogeneity. In Aim 1, this system is used to quantify and model single macrophage gene expression
kinetics following dynamic IFNγ stimulus and to elucidate the mechanism of signal decoding. This is done by
applying IFNγ stimulus of varying amplitude and duration to the macrophages and simultaneously tracking
expression kinetics of three components of the GBP1 and NOS2 networks in the same single cells over time. A
mathematical model will be developed to describe these responses, predict the response to perturbation, and
will be tested using inducible promoters and inhibitors of chromatin regulators to perturb the decoding. Aim 2
investigates the connection between cell-to-cell variability in gene expression kinetics and heterogeneous Mtb
infection outcomes. This is done by infecting fluorescent reporter macrophage cell lines with Mtb marked by a
viability reporter and assaying both gene expression kinetics and infection outcomes in single cells. The
completion of these aims will provide a quantitative understanding of the mechanisms by which macrophages
decode dynamic IFNγ stimuli into time-variant gene expression patterns, as well as mechanistic insight into the
sources of heterogeneity in the outcomes of Mtb infection.
项目总结
项目成果
期刊论文数量(0)
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Beverly Naigles其他文献
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{{ truncateString('Beverly Naigles', 18)}}的其他基金
Tracking the dynamics of the macrophage response to interferon-gamma at a single-cell level
在单细胞水平追踪巨噬细胞对干扰素γ反应的动态
- 批准号:
10757599 - 财政年份:2022
- 资助金额:
$ 3.97万 - 项目类别:
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