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
项目总结/摘要
树突状细胞(DC)在靶向病原体的免疫应答中发挥关键作用,
抗原呈递细胞和分泌有效的先天免疫和炎性细胞因子。它们分化
从骨髓中发现的造血干细胞分化为多种亚型,
炎症/适应性免疫或更多先天免疫功能。这些分化的失调
过程是骨髓增生性疾病(MPD)的根本原因,包括急性髓性白血病(AML),
和炎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
用关键的髓样分化和生长因子GM-CSF和Flt 3L进行体外概括,先前的工作已经
表明NF κ B B信号系统是一个重要的调节器。然而,鉴于这一多方面的复杂性,
转录因子,多调节信号系统,其在亚型分化,增殖,
疾病仍然知之甚少。
在建议的项目中,我们将研究NF κ B B控制在协调分化程序中的作用,
树突状细胞分为两种发育途径。根据我们的初步结果,我们提出了
总体假设是在DC过程中NF κ B B信号系统的适当逐步组装
分化途径对于分阶段增殖和成熟至关重要;而经典的I型B β,-β,-β介导
在短暂的NF-κ B B炎症反应中,最近描述的NF-κ B体起着关键的缓冲作用,
在DC分化中的协调作用。I型糖尿病的失调会导致严重的,但令人惊讶的是,
两种DC发育途径中的表型。
我们将联合收割机结合一个实验验证的数学模型NF κ B B信号转导过程中树突状细胞
分化和功能,定量生化,流式细胞仪,和活细胞荧光
显微镜,干涉测量和谱系跟踪研究涉及敲入报告小鼠,和一些新的
遗传小鼠品系,以揭示与骨髓增生相关的NF κ B B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生物多样性的见解,
该法规旨在检查患者样本以及潜在药物靶点的疗效和风险。
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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资助金额:$71.0万
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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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资助金额:$25.7万
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负责人:Alexander Hoffmann
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Bruins in Genomics: Dental, Oral & Craniofacial Research Training Program (BIG DOC)
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批准号:10328979
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资助金额:$31.72万
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Cell decision underlying B-cell immune responses
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批准号:10330546
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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
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依托单位:
The NFkB System in Dendritic Cells
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批准号:10375381
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项目类别:
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资助金额:$41.52万
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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:
Core D: Computational
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批准号:10000880
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项目类别:
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资助金额:$11.91万
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财政年份:2017
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负责人:Alexander Hoffmann
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依托单位:
Coordinated dynamic regulation and function of IRF transcription factors
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批准号:10155390
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项目类别:
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资助金额:$39.0万
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财政年份:2017
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负责人:Alexander Hoffmann
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依托单位:
Core D: Computational
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批准号:10225362
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项目类别:
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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
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依托单位:
NFkB Signaling in Macrophages
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批准号:10054972
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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
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批准号:9228009
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项目类别:
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资助金额:$23.1万
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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:
Understanding dynamical coding by NFkB
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批准号:9223713
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项目类别:
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资助金额:$61.07万
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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:
NGS Data Analysis Skills for the Biosciences Pipeline
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批准号:9044430
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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
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依托单位:
Epigenomic control of RNA splicing
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批准号:8815662
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项目类别:
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资助金额:$30.8万
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财政年份:2014
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负责人:Alexander Hoffmann
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依托单位:
Epigenomic control of RNA splicing
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批准号:8921202
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项目类别:
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资助金额:$30.8万
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财政年份:2014
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负责人:Alexander Hoffmann
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依托单位:
SEED PROJECT
-
批准号:8151848
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财政年份:2010
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负责人:Alexander Hoffmann
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依托单位:
Center for Systems Biology of Cellular Stress Responses
-
批准号:8145605
-
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资助金额:$297.25万
-
财政年份:2010
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负责人:Alexander Hoffmann
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依托单位:
Center for Systems Biology of Cellular Stress Responses
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批准号:8332812
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资助金额:$295.64万
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财政年份:2010
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负责人:Alexander Hoffmann
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依托单位:
Center for Systems Biology of Cellular Stress Responses
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批准号:8608685
-
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资助金额:$5.44万
-
财政年份:2010
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负责人:Alexander Hoffmann
-
依托单位:
CORE E: EDUCATION
-
批准号:8151886
-
项目类别:
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资助金额:$3.09万
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财政年份:2010
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负责人:Alexander Hoffmann
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依托单位:
海外基金