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:9889158
- 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 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:ActinsActomyosinAdaptor Signaling ProteinAdenomatous Polyposis Coli 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 RNAStimulusStructureSurfaceSystemT-Cell ActivationT-Cell ReceptorT-LymphocyteTechniquesTestingTherapeuticTraction Force MicroscopyTranslatingWorkadaptive immune responsebasecancer cellcell killingcytokinecytotoxic CD8 T cellsgenetic regulatory proteinhuman diseaseimmunological synapsein vivoknock-downmechanical forcemechanical propertiesmechanotransductionmutantneoplastic 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.
由粘附和信号传导受体介导的细胞-细胞相互作用是高度动态的,并且受到粘附和信号传导受体的影响。
在界面处施加实质性机械力的细胞骨架运动。细胞如何联合收割机机械地
和生物化学信号来执行特定的功能还没有很好的理解。免疫系统的细胞
一个令人信服的背景下,研究力的传输和机械传感,因为他们是结构动态
是生化信息传递的场所。T细胞信号传导与细胞骨架密切相关,
很明显,肌动蛋白细胞骨架在T细胞受体上施加的力被转换成生化信号,
导致T细胞活化。然而,这些力量被调节的分子机制以及如何调节
它们对T细胞功能的贡献仍然不清楚。在这里,我们建议剖析的相互作用和活动,
位于肌动蛋白和微管(MT)动力学交叉点的蛋白质,以促进我们对
力的产生和机械感应。我们假设动态微管调节T细胞
细胞骨架和近端信号都通过1)调节板状伪足中的肌动蛋白聚合动力学
以及板层中结构的组装和2)调节RhoA激活导致肌球蛋白收缩性
和力量的生成。最终,我们假设MT/肌动蛋白相互作用有助于T细胞的能力,
使它们的激活和效应器功能适应靶细胞的硬度。我们的第一个目标是
通过探测MT之间的特异性相互作用,研究MT调节肌动蛋白动力学的机制。
和肌动蛋白通过+TIP蛋白。我们将结合联合收割机光遗传学技术与突变来探测特定的相互作用
MT和肌动蛋白之间的联系。我们的第二个目标是剖析联系的机制
肌球蛋白驱动的收缩力产生的动态MT。我们将联合收割机结合RhoA的光遗传学控制
激活和抑制与定量成像和牵引力显微镜,以阐明时空
在T细胞活化期间RhoA活化的特征。我们将使用新型传感器来检测GEF-H1的活性,
突变以确定其在MT/肌动蛋白偶联、力产生和T细胞信号传导中的作用。最后,我们将表演
在功能背景下用小鼠细胞进行的研究,以检验肌动球蛋白动力学的调节
和收缩性调节细胞毒性T淋巴细胞活化的机械协调,
杀死癌细胞我们提出的研究将阐明机械刺激和生化信号是如何
在免疫反应中结合。此外,本提案中研究的具体途径与以下方面有关:
一些免疫缺陷和淋巴瘤的进展,从而将有助于更好地了解
它们的功能障碍如何导致人类疾病,从而为免疫干预提供新的靶点,
疗法
项目成果
期刊论文数量(0)
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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:
10359737 - 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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