The NFkB System in Dendritic Cells
The NFkB System in Dendritic Cells
批准号:
9891942
负责人:
Alexander Hoffmann
金额:
$43.43万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-04-03 至 2023-03-31
关键词:
Acute Myelocytic LeukemiaAnimalsAntigen-Presenting CellsBiochemicalBone MarrowBuffersCell Culture TechniquesCell DeathCell Differentiation processCell LineageCell physiologyCellsClinicalComplexCouplingDendritic Cell PathwayDendritic CellsDependenceDevelopmentDifferentiation and GrowthDiseaseDrug TargetingEosinophilic GranulomaEpigenetic ProcessEquilibriumEventFLT3 ligandFluorescence MicroscopyGeneticGenetic studyGiant CellsGranulocyte-Macrophage Colony-Stimulating FactorGrowth FactorHematopoietic stem cellsHomeostasisHumanImmuneImmune TargetingImmune responseInflammatoryInflammatory ResponseInterferometryInterferon Type IIKineticsKnock-inMalignant NeoplasmsMeasurementMediatingModelingMolecularMolecular WeightMouse StrainsMusMutant Strains MiceMyelogenousMyelopoiesisMyeloproliferative diseasePathway interactionsPatientsPharmacologyPhasePhenotypePlant RootsPlayProcessPublishingRegulationReporterResolutionRiskRoleSamplingSignal TransductionSystemSystems BiologyTestingTherapeuticWorkacute myeloid leukemia cellbasechronic inflammatory diseasecytokinedimerhematopoietic stem cell differentiationhuman diseaseimmune functioninhibitor/antagonistinnate immune functioninsightleukemialive cell microscopymathematical modelnetwork modelsnovelpathogenpredictive modelingprogramsresponsetranscription factor
中文摘要
项目摘要/摘要
树突状细胞(DC)在针对病原体的靶向免疫反应中发挥关键作用,两者都通过以下方式发挥作用
通过分泌强大的先天免疫和炎性细胞因子。他们的区别在于
从在骨髓中发现的造血干细胞转变为多个亚型
炎症/适应性免疫或更多的先天免疫功能。对这些差异的错误调控
过程是包括急性髓系白血病(AML)在内的骨髓增生性疾病(MPD)的根本原因,
和炎症性疾病朗格汉斯细胞组织细胞增生症(LCH)。这些分化过程可能是
概述了关键的髓系分化和生长因子GM-CSF和Flt3L的体外实验,以及先前的工作
说明了NFB信号系统是一种重要的调节因子。然而,考虑到这种多方面的复杂性-
转录因子,多调节信号系统,其在亚型分化、增殖和蛋白合成中的作用
人们对这种疾病仍然知之甚少。
在拟议的项目中,我们将研究核因子B控制在协调分化计划中的作用
树突状细胞分为两条发育途径。基于我们的初步结果,我们建议
最重要的假设是,在DC过程中,NFB信号系统正确地逐步组装
分化途径是促进细胞增殖和成熟的关键途径,而经典的I--B-,-,-起着中介作用
暂时性的核因子B炎症反应,最近描述的IBome发挥了关键的缓冲和
在DC分化中的协调作用。IBome的错误调控导致了严重但令人惊讶的不同
DC两条发育途径的表型。
我们将结合一个经过实验验证的树突状细胞中核因子B信号的数学模型
分化和功能,用定量生化、流式细胞仪和活细胞荧光
显微镜、干涉测量和谱系追踪研究,涉及敲门报告小鼠,以及一些新的
遗传性小鼠品系揭示与骨髓增殖症相关的核因子B调控失调的分子基础
疾病(MPD)和朗格汉斯细胞组织细胞增生症(LCH)。我们将应用这些关于iBome的见解
检查患者样本和潜在药物靶标的有效性和风险的法规。
英文摘要
Project Summary/Abstract
Dendritic cells (DCs) play key roles in targeting immune responses to pathogens, both by functioning as
antigen presenting cells and by secreting potent innate immune and inflammatory cytokines. They differentiate
from hematopoietic stem cells found in the bone marrow into multiple subtypes that have more
inflammatory/adaptive immune or more innate immune functions. Misregulation of these differentiation
processes is the root cause of myeloproliferative disorders (MPD) including acute myeloid leukemia (AML),
and the inflammatory disease Langerhans Cell Histiocytosis (LCH). These differentiation processes may be
recapitulated ex vivo with key myeloid differentiation and growth factors GM-CSF and Flt3L, and prior work has
shown that the NFB signaling system is an important regulator. Yet given the complexity of this multi-
transcription factor, multi-regulator signaling system, its roles in subtype-differentiation, proliferation, and in
disease remain poorly understood.
In the proposed project we will examine the role of NFB control in coordinating differentiation programs of
dendritic cells into two developmental pathways. Based on our preliminary results we propose the
overarching hypothesis that proper stepwise assembly of the NFB signaling system during DC
differentiation pathways is critical for phasing proliferation and maturation; while classical IB, -, - mediate
transient NFB inflammatory responses, the recently described IBsome plays a critical buffering and
coordinating role in DC differentiation. Misregulation of the IBsome leads to severe but surprisingly different
phenotypes in the two DC developmental pathways.
We will combine an experimentally validated mathematical model of NFB signaling during dendritic cell
differentiation and function, with quantitative biochemical, flow cytometric, and live cell fluorescence
microscopy, interferometry and lineage tracking studies involving knockin reporter mice, and a number of novel
genetic mouse strains to uncover the molecular basis of NFB misregulation associated with myeloprolferative
disorders (MPD) and Langerhans Cell Histiocytosis (LCH). We will apply these insights about the IBsome
regulation to examine patient samples and the efficacy and risks of potential drug targets.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Characterizing functional states of macrophages via their stimulus-responses
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批准号:10737449
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项目类别:
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资助金额:$71.0万
-
财政年份:2023
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负责人:Alexander Hoffmann
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依托单位:
Bruins in Genomics: Dental, Oral & Craniofacial Research Training Program (BIG DOC)
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批准号:10540402
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项目类别:
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资助金额:$25.7万
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财政年份:2021
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负责人:Alexander Hoffmann
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依托单位:
Bruins in Genomics: Dental, Oral & Craniofacial Research Training Program (BIG DOC)
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批准号:10328979
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项目类别:
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资助金额:$31.72万
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财政年份:2021
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负责人:Alexander Hoffmann
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依托单位:
Cell decision underlying B-cell immune responses
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批准号:10330546
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项目类别:
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资助金额:$41.9万
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财政年份:2018
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负责人:Alexander Hoffmann
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依托单位:
Cell decision underlying B-cell immune responses
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批准号:10094180
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项目类别:
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资助金额:$42.7万
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财政年份:2018
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负责人:Alexander Hoffmann
-
依托单位:
The NFkB System in Dendritic Cells
-
批准号:10375381
-
项目类别:
-
资助金额:$41.52万
-
财政年份:2018
-
负责人:Alexander Hoffmann
-
依托单位:
Core D: Computational
-
批准号:10000880
-
项目类别:
-
资助金额:$11.91万
-
财政年份:2017
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负责人:Alexander Hoffmann
-
依托单位:
Coordinated dynamic regulation and function of IRF transcription factors
-
批准号:10155390
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项目类别:
-
资助金额:$39.0万
-
财政年份:2017
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负责人:Alexander Hoffmann
-
依托单位:
Core D: Computational
-
批准号:10225362
-
项目类别:
-
资助金额:$12.47万
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财政年份:2017
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负责人:Alexander Hoffmann
-
依托单位:
NFkB Signaling in Macrophages
-
批准号:10054972
-
项目类别:
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资助金额:$38.5万
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财政年份:2016
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负责人:Alexander Hoffmann
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依托单位:
Roles of RelB in tuning inflammatory and innate immune responses
-
批准号:9228009
-
项目类别:
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资助金额:$23.1万
-
财政年份:2016
-
负责人:Alexander Hoffmann
-
依托单位:
Understanding dynamical coding by NFkB
-
批准号:9223713
-
项目类别:
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资助金额:$61.07万
-
财政年份:2016
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负责人:Alexander Hoffmann
-
依托单位:
NGS Data Analysis Skills for the Biosciences Pipeline
-
批准号:9044430
-
项目类别:
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资助金额:$16.0万
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财政年份:2015
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负责人:Alexander Hoffmann
-
依托单位:
Epigenomic control of RNA splicing
-
批准号:8815662
-
项目类别:
-
资助金额:$30.8万
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财政年份:2014
-
负责人:Alexander Hoffmann
-
依托单位:
Epigenomic control of RNA splicing
-
批准号:8921202
-
项目类别:
-
资助金额:$30.8万
-
财政年份:2014
-
负责人:Alexander Hoffmann
-
依托单位:
SEED PROJECT
-
批准号:8151848
-
项目类别:
-
资助金额:$15.45万
-
财政年份:2010
-
负责人:Alexander Hoffmann
-
依托单位:
Center for Systems Biology of Cellular Stress Responses
-
批准号:8145605
-
项目类别:
-
资助金额:$297.25万
-
财政年份:2010
-
负责人:Alexander Hoffmann
-
依托单位:
Center for Systems Biology of Cellular Stress Responses
-
批准号:8332812
-
项目类别:
-
资助金额:$295.64万
-
财政年份:2010
-
负责人:Alexander Hoffmann
-
依托单位:
Center for Systems Biology of Cellular Stress Responses
-
批准号:8608685
-
项目类别:
-
资助金额:$5.44万
-
财政年份:2010
-
负责人:Alexander Hoffmann
-
依托单位:
CORE E: EDUCATION
-
批准号:8151886
-
项目类别:
-
资助金额:$3.09万
-
财政年份:2010
-
负责人:Alexander Hoffmann
-
依托单位:
海外基金