Microtubule regulation of actomyosin dynamics and force generation in T lymphocytes
T 淋巴细胞中肌动球蛋白动力学和力产生的微管调节
基本信息
- 批准号:10359737
- 负责人:
- 金额:$ 30.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-03-15 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:APC geneActinsActomyosinAdaptor Signaling ProteinAdhesionsAdhesivesAntigensBindingBiochemicalBiologicalBiomechanicsCD8B1 geneCell CommunicationCell physiologyCellsCharacteristicsClonal ExpansionCoupledCouplingCuesCytoskeletonCytotoxic T-LymphocytesDevelopmentEnvironmentFamilyFilamentFunctional disorderFutureGelGenerationsGoalsGuanineGuanine Nucleotide Exchange FactorsHumanImmune responseImmune systemImmunologic Deficiency SyndromesImmunotherapyIn VitroInfectionInflammatoryInterleukin-12Interleukin-2InterventionLeadLinkLymphocyte ActivationLymphomaMaintenanceMechanicsMediatingMicrotubulesMolecularMovementMusMutationMyosin ATPaseOpticsPathway interactionsPlayPlus End of the MicrotubuleProcessProteinsReceptor SignalingRegulationRho-associated kinaseRoleSignal PathwaySignal TransductionSiteSmall Interfering RNAStructureSurfaceSystemT-Cell ActivationT-Cell ReceptorT-LymphocyteTechniquesTestingTherapeuticTraction Force MicroscopyTranslatingWorkadaptive immune responsebasecancer cellcell killingcytokinecytotoxic CD8 T cellsgenetic regulatory proteinhuman diseaseimmunological synapsein vivoknock-downmechanical forcemechanical propertiesmechanical stimulusmechanotransductionmutantneoplastic cellnovelnovel strategiesoptogeneticsphysical propertypolymerizationquantitative imagingresponsesensorspatiotemporaltransmission processtumor
项目摘要
Cell-cell interactions, mediated by adhesion and signaling receptors, are highly dynamic and subject to
cytoskeletal movements that impart substantial mechanical force at the interface. How cells combine mechanical
and biochemical signals to carry out specific functions is not well understood. Cells of the immune system present
a compelling context for studying force transmission and mechanosensing because they are structurally dynamic
and are sites of biochemical information transfer. T cell signaling is closely linked to the cytoskeleton, and it is
evident that forces applied by the actin cytoskeleton at the T cell receptor are transduced to biochemical signaling
leading to T cell activation. However, the molecular mechanisms by which these forces are regulated and how
they contribute to T cell function remain obscure. Here, we propose to dissect the interactions and activities of
proteins that reside at the intersection of actin and microtubule (MT) dynamics to advance our understanding of
force generation and mechanosensing in T cells. We hypothesize that dynamic microtubules modulate the T cell
cytoskeleton and proximal signaling both by 1) regulating actin polymerization dynamics in the lamellipodium
and the assembly of structures in the lamella and 2) regulating RhoA activation leading to myosin contractility
and force generation. Ultimately, we hypothesize that MT/actin interactions contribute to the ability of T cells to
adapt their activation and effector function in response to the stiffness of target cells. Our first goal will be to
examine the mechanisms by which MT regulate actin dynamics by probing the specific interactions between MT
and actin via +TIP proteins. We will combine optogenetic techniques with mutations to probe specific interactions
between MT and actin that regulate T cell activation. Our second goal will be to dissect the mechanisms that link
dynamic MTs to myosin driven contractile force generation. We will combine optogenetic control of RhoA
activation and inhibition with quantitative imaging and traction force microscopy to elucidate the spatiotemporal
characteristics of RhoA activation during T cell activation. We will use novel sensors for GEF-H1 activity and
mutations to establish its role in MT/actin coupling, force generation and T cell signaling. Finally, we will perform
studies with mouse cells in a functional context to test the hypothesis that regulation of actomyosin dynamics
and contractility tunes the mechanical coordination of cytotoxic T lymphocyte activation and their efficacy in
killing cancer cells. Our proposed studies will clarify how mechanical stimuli and biochemical signaling are
coupled during the immune response. Furthermore, the specific pathways studied in this proposal are linked to
a number of immunodeficiencies and lymphoma progression and thus will help lead to a better understanding of
how their dysfunction can contribute to human disease, thus providing new targets for intervention in immune
therapy.
由粘附和信号受体介导的细胞-细胞相互作用是高度动态的,并受
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Cytotoxic T Lymphocyte Activation Signals Modulate Cytoskeletal Dynamics and Mechanical Force Generation.
- DOI:10.3389/fimmu.2022.779888
- 发表时间:2022
- 期刊:
- 影响因子:7.3
- 作者:Pathni A;Özçelikkale A;Rey-Suarez I;Li L;Davis S;Rogers N;Xiao Z;Upadhyaya A
- 通讯作者:Upadhyaya A
Phase separation in transcription factor dynamics and chromatin organization.
- DOI:10.1016/j.sbi.2021.06.009
- 发表时间:2021-12
- 期刊:
- 影响因子:6.8
- 作者:Wagh K;Garcia DA;Upadhyaya A
- 通讯作者:Upadhyaya A
Three-dimensional structured illumination microscopy with enhanced axial resolution.
- DOI:10.1038/s41587-022-01651-1
- 发表时间:2023-09
- 期刊:
- 影响因子:46.9
- 作者:Li, Xuesong;Wu, Yicong;Su, Yijun;Rey-Suarez, Ivan;Matthaeus, Claudia;Updegrove, Taylor B. B.;Wei, Zhuang;Zhang, Lixia;Sasaki, Hideki;Li, Yue;Guo, Min;Giannini, John P. P.;Vishwasrao, Harshad D. D.;Chen, Jiji;Lee, Shih-Jong J.;Shao, Lin;Liu, Huafeng;Ramamurthi, Kumaran S. S.;Taraska, Justin W. W.;Upadhyaya, Arpita;La Riviere, Patrick;Shroff, Hari
- 通讯作者:Shroff, Hari
Nanotopography modulates cytoskeletal organization and dynamics during T cell activation.
- DOI:10.1091/mbc.e21-12-0601
- 发表时间:2022-09-01
- 期刊:
- 影响因子:3.3
- 作者:Wheatley, Brittany A.;Rey-Suarez, Ivan;Hourwitz, Matt J.;Kerr, Sarah;Shroff, Hari;Fourkas, John T.;Upadhyaya, Arpita
- 通讯作者:Upadhyaya, Arpita
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Arpita Upadhyaya其他文献
Arpita Upadhyaya的其他文献
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{{ truncateString('Arpita Upadhyaya', 18)}}的其他基金
Cellular mechanotransduction - from the immune response to transcriptional regulation
细胞机械转导 - 从免疫反应到转录调节
- 批准号:
10693137 - 财政年份:2022
- 资助金额:
$ 30.78万 - 项目类别:
Cellular mechanotransduction - from the immune response to transcriptional regulation
细胞机械转导 - 从免疫反应到转录调节
- 批准号:
10406710 - 财政年份:2022
- 资助金额:
$ 30.78万 - 项目类别:
Supplement request for Cellular mechanotransduction - from the immune response to transcriptional regulation
细胞机械转导的补充请求 - 从免疫反应到转录调控
- 批准号:
10799068 - 财政年份:2022
- 资助金额:
$ 30.78万 - 项目类别:
Microtubule regulation of actomyosin dynamics and force generation in T lymphocytes
T 淋巴细胞中肌动球蛋白动力学和力产生的微管调节
- 批准号:
9889158 - 财政年份:2019
- 资助金额:
$ 30.78万 - 项目类别:
Microtubule regulation of actomyosin dynamics and force generation in T lymphocytes
T 淋巴细胞中肌动球蛋白动力学和力产生的微管调节
- 批准号:
10115767 - 财政年份:2019
- 资助金额:
$ 30.78万 - 项目类别:
Nanotopographic modulation of B cell signaling activation
B 细胞信号传导激活的纳米拓扑调节
- 批准号:
9281650 - 财政年份:2016
- 资助金额:
$ 30.78万 - 项目类别:
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$ 30.78万 - 项目类别:
Priority Programmes
STRUCTURE/INTERACTIONS OF ACTINS AND ACTIN-BINDING PROTEIN
肌动蛋白和肌动蛋白结合蛋白的结构/相互作用
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