Functional roles of lipid domains in B cell signaling
Functional roles of lipid domains in B cell signaling
批准号:
10393588
负责人:
Sarah L Veatch
金额:
$28.31万
依托单位国家:
美国
项目类别:
财政年份:
2014
资助国家:
美国
项目状态:
已结题
起止时间:
2014-05-01 至 2024-04-30
关键词:
ActinsAdaptive Immune SystemAdaptor Signaling ProteinAffinityAgingAmino Acid MotifsAntigensApoptosisAutoimmunityB cell differentiationB-Cell ActivationB-Cell Antigen ReceptorB-Cell DevelopmentB-LymphocytesBiochemicalBiosensorCell Surface ProteinsCell Surface ReceptorsCell membraneCell surfaceCellsCellular biologyCharacteristicsChemicalsCouplingCytoskeletonDataDecision MakingDefectDevelopmentDiseaseDrug TargetingElementsEventExposure toFluorescenceFundingFutureGoalsHealthHeterogeneityHumanImageImmune System DiseasesImmune responseImmune systemImmunodeficiency and CancerImmunologic Deficiency SyndromesImmunotherapeutic agentKnowledgeLateralLeadLigandsLightLipidsLiteratureLymphomaMAP Kinase GeneMediatingMembraneMembrane ProteinsMethodologyMicroscopyMissionModelingOutcomePathway interactionsPeripheralPharmaceutical PreparationsPhasePhosphoric Monoester HydrolasesPhosphotransferasesPlayReceptor ActivationReceptor SignalingRegulationReportingResearchResolutionRoleSignal TransductionSpatial DistributionStructureTechniquesTechnologyTestingTyrosine PhosphorylationUnited States National Institutes of HealthVesicleWorkcancer cellcrosslinkeffective interventionexperimental studyextracellularhuman diseaseimmune functionimmunoregulationinnovationmembrane modelnovel strategiesoptogeneticsphysical modelpredictive modelingpreferencepreventreceptorreceptor functionreconstitutionrelease of sequestered calcium ion into cytoplasmresponsescaffoldsrc-Family Kinasestooltyrosine receptor
中文摘要
项目总结
B细胞感知和操纵众多细胞表面受体的横向组织,以促进
它们在免疫系统中的功能作用。受体聚集作为信号启动的一种物理模式是
在B细胞中普遍存在,但相应的感知和控制聚集的一般机制
胞内成分尚不清楚。对聚集性B细胞信号转导机制的理解
事件是必不可少的,因为它们在免疫功能中发挥着重要作用,缺陷会导致疾病,如
癌症和免疫缺陷以及广泛使用的免疫治疗药物利用了这些机制。目标是
这项工作的重点是开发一个框架,描述受体组织是如何与受体功能联系在一起的
B细胞表面受体的一类,用有序的膜结构域进行划分。工作假说是
有序结构域稳定为启动和调节不同的B蛋白提供了基本范式
细胞信号反应。这项拟议的研究是由B细胞受体(BCR)预测模型指导的
在上一个资金周期中开发的信号传递,并在实验中测试了该模型的扩展预测
不仅仅是BCR信号。在广泛的初步数据指导下,将追求三个具体目标:1)
建立聚集B细胞表面蛋白激活信号的一般机制,2)调节B细胞
通过光遗传控制支架元件的细胞膜组织和信号传递,以及3)识别
膜结构域在bcr信号中的免疫调节作用。第一个目标是建立一个将军
一种传感机制,描述了通过聚集15个以上不同的B细胞表面蛋白而启动的信号
它们在文献中被报告为具有有序结构域的分区。第二个目标将定义脚手架如何
分子模板功能膜组织跨质膜小叶及其贡献
这种对配体非依赖信号的影响。第三个目标将确定并隔离类似阶段的角色
膜结构域在下游细胞决策中发挥作用,通过调制通过
BCR。所有目标都使用定量超分辨率荧光定位显微镜技术
在化学固定细胞和活细胞中检测微妙的区域介导的相互作用的灵敏度。建议的工作是
创新性,因为它应用了膜组织的预测模型,并利用了
超分辨率成像、生物传感器技术和光遗传学。一种具有广泛适用性的机械模型
B细胞信号将推动基础B细胞生物学的未来进展,阐明
几种广泛使用的B细胞靶向药物的疗效,并为免疫治疗提供了新的途径
疾病。
英文摘要
PROJECT SUMMARY
B cells sense and manipulate the lateral organization of numerous cell surface receptors in order to facilitate
their functional roles within the immune system. Receptor clustering as a physical mode of signal initiation is
ubiquitous in B cells, yet the corresponding general mechanisms by which clustering is sensed and controlled
by intracellular components are unknown. A mechanistic understanding of clustering-mediated B cell signaling
events is essential because they play important roles in immune function, defects lead to diseases such as
cancer and immunodeficiency, and widely used immunotherapeutic drugs exploit these mechanisms. The goal
of this work is to develop a framework that describes how receptor organization is tied to receptor functions for
the class of B cell surface receptors that partition with ordered membrane domains. The working hypothesis is
that ordered domain stabilization provides a fundamental paradigm for the initiation and regulation of diverse B
cell signaling responses. The proposed research is guided by a predictive model of B cell receptor (BCR)
signaling developed in the previous funding cycle and experimentally tests predictions of this model extended
beyond BCR signaling alone. Guided by extensive preliminary data, three specific aims will be pursued: 1)
Establish a generalized mechanism of signaling activated by clustering B cell surface proteins, 2) Modulate B
cell membrane organization and signaling through optogenetic control of scaffolding elements, and 3) Identify
immunomodulatory roles facilitated by membrane domains in BCR signaling. The first aim will establish a general
sensing mechanism that describes signals initiated via clustering of more than 15 distinct B cell surface proteins
that are reported in the literature to partition with ordered domains. The second aim will define how scaffolding
elements template functional membrane organization that spans plasma membrane leaflets and the contribution
of this effect to ligand-independent signaling. The third aim will identify and isolate the roles that phase-like
membrane domains play in downstream cellular decision-making by modulating signals initiated through the
BCR. All aims use quantitative super-resolution fluorescence localization microscopy techniques with the
sensitivity to detect subtle domain-mediated interactions in chemically fixed and live cells. The proposed work is
innovative because it applies predictive models of membrane organization and exploits recent advances in
super-resolution imaging, biosensor technology, and optogenetics. A broadly applicable mechanistic model for
B cell signaling will drive future advances in basic B cell biology, elucidate the mechanisms underlying the
efficacy of several widely used B cell-targeted drugs, and provide new approaches for the treatment of immune
diseases.
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DOI:
10.1371/journal.pone.0140925
发表时间:
2015
期刊:
PloS one
影响因子:
3.7
作者:
[Raghunathan,Krishnan, Ahsan,Aarif, Ray,Dipankar, Nyati,MukeshK, Veatch,SarahL]
通讯作者:
Veatch,SarahL
DOI:
10.1016/j.bpj.2016.06.039
发表时间:
2016-08-09
期刊:
BIOPHYSICAL JOURNAL
影响因子:
3.4
作者:
[Machta, Benjamin B., Gray, Ellyn, Veatch, Sarah L.]
通讯作者:
Veatch, Sarah L.
DOI:
10.1016/j.bpr.2021.100008
发表时间:
2021-09-08
期刊:
Biophysical reports
影响因子:
--
作者:
[Fazekas, Frank J, Shaw, Thomas R, Veatch, Sarah L]
通讯作者:
Veatch, Sarah L
DOI:
10.1016/j.jmb.2016.08.022
发表时间:
2016-12-04
期刊:
JOURNAL OF MOLECULAR BIOLOGY
影响因子:
5.6
作者:
[Levental, Ilya, Veatch, Sarah L.]
通讯作者:
Veatch, Sarah L.
DOI:
10.1038/ncomms8347
发表时间:
2015-06-12
期刊:
Nature communications
影响因子:
16.6
作者:
[Stone MB, Veatch SL]
通讯作者:
Veatch SL
共 16 条
Ion channel regulation by heterogeneous membranes
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批准号:10473794
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项目类别:
-
资助金额:$26.08万
-
财政年份:2019
-
负责人:Sarah L Veatch
-
依托单位:
Ion channel regulation by heterogeneous membranes
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批准号:10256046
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项目类别:
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资助金额:$26.13万
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财政年份:2019
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负责人:Sarah L Veatch
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依托单位:
Ion channel regulation by heterogeneous membranes
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批准号:10016343
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项目类别:
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资助金额:$26.17万
-
财政年份:2019
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负责人:Sarah L Veatch
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依托单位:
Functional roles of lipid domains in B cell signaling
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批准号:10183265
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项目类别:
-
资助金额:$29.2万
-
财政年份:2014
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负责人:Sarah L Veatch
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依托单位:
Functional roles of lipid domains in B cell signaling
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批准号:9921409
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项目类别:
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资助金额:$29.51万
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财政年份:2014
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负责人:Sarah L Veatch
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依托单位:
Functional roles of lipids in early B cell receptor signaling SUPPLEMENT
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批准号:9276225
-
项目类别:
-
资助金额:$15.0万
-
财政年份:2014
-
负责人:Sarah L Veatch
-
依托单位:
Functional roles of lipids in early B cell receptor signaling.
-
批准号:8668648
-
项目类别:
-
资助金额:$28.95万
-
财政年份:2014
-
负责人:Sarah L Veatch
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依托单位:
Functional roles of lipids in early B cell receptor signaling.
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批准号:9058146
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项目类别:
-
资助金额:$28.83万
-
财政年份:2014
-
负责人:Sarah L Veatch
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依托单位:
Mechanistic studies of membrane lateral organization in cell plasma membranes.
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批准号:8146018
-
项目类别:
-
资助金额:$24.65万
-
财政年份:2009
-
负责人:Sarah L Veatch
-
依托单位:
Mechanistic studies of membrane lateral organization in cell plasma membranes.
-
批准号:8133576
-
项目类别:
-
资助金额:$24.9万
-
财政年份:2009
-
负责人:Sarah L Veatch
-
依托单位:
Mechanistic studies of membrane lateral organization in cell plasma membranes.
-
批准号:8333403
-
项目类别:
-
资助金额:$24.65万
-
财政年份:2009
-
负责人:Sarah L Veatch
-
依托单位:
Mechanistic studies of membrane lateral organization in cell plasma membranes.
-
批准号:7659731
-
项目类别:
-
资助金额:$8.99万
-
财政年份:2009
-
负责人:Sarah L Veatch
-
依托单位:
海外基金