Cystoskeletal Remodeling During T Cell Activation
Cystoskeletal Remodeling During T Cell Activation
批准号:
7333282
负责人:
Janis K. Burkhardt
金额:
$40.4万
依托单位国家:
美国
项目类别:
财政年份:
2007
资助国家:
美国
项目状态:
已结题
起止时间:
2007-01-01 至 2011-12-31
关键词:
ActinsAffectAgonistArchitectureAutoimmune DiseasesBindingBiochemicalBiological AssayBoxingCalciumCellsChromosome PairingComplexConditionCytoskeletonDefectDoseEEF1A2 geneEventExhibitsGene ExpressionGenetic PolymorphismGoalsImmuneImmunologic Deficiency SyndromesIn VitroIndividualInterleukin-2Knock-outLearningLifeLinkLupusMembrane MicrodomainsMicrofilamentsMicroscopyMolecularMolecular ConformationMovementMusMutationPathway interactionsPeptidesPhenotypePhosphorylationPhysiologicalPlayProcessProductionProtein Binding DomainProteinsRangeRegulationResolutionRoleSignal TransductionStructureSynapsesT-Cell ActivationT-LymphocyteTestingTimeTyrosine PhosphorylationVariantYWHAQ geneadapter proteincell typecomparativecytokinegenetic regulatory proteinin vitro Assayin vivomutantnovel strategiespolymerizationresearch studyresponsesmall hairpin RNAsynaptogenesis
中文摘要
T细胞与APCs的相互作用诱导免疫系统中肌动蛋白细胞骨架的急剧重塑
突触这一过程是T细胞活化和严重免疫缺陷或
自身免疫性疾病由肌动蛋白调节分子如WASP和HS 1的突变引起。本研究将
检验HS 1、WASP和WASP以协调方式协调肌动蛋白的中心假设
免疫突触的动力学,使得每个组件在调节肌动蛋白中发挥独特的作用
架构,同时调节其他人的功能。在目标1中,我们将询问这些蛋白质在多大程度上
直接相互作用,并寻求将HS 1置于涉及肌动蛋白,WASP,
Itk和Vav。我们将探讨这些肌动蛋白调节分子如何影响彼此的稳定性、靶向和
构象,并分析活T细胞中荧光标记蛋白质的运动。在目标2中,我们
使用缺乏单个肌动蛋白调节蛋白的细胞在T细胞活化期间进行功能分析。
将进行肌动蛋白动力学和皮层肌动蛋白EM的视频分析,以测试WASP和
β 1协同驱动肌动蛋白聚合,而HS 1则起稳定肌动蛋白丝的作用。此外,肌动蛋白-
从免疫突触形成到增殖和细胞因子产生的依赖性T细胞应答
将被评估。在目标3中,我们将通过在大肠杆菌中表达突变体来进行HS 1的结构-功能分析。
HS 1缺陷型T细胞和测定肌动蛋白反应和T细胞活化的其他方面。除了
测试结构域和蛋白质-蛋白质相互作用基序,我们将测试狼疮相关插入的功能
多态最后,我们将分析HS 1酪氨酸磷酸化,并测试生理效应,
非磷酸化点突变体。总之,这些研究将推动该领域向分子水平发展。
了解免疫突触的肌动蛋白动力学是如何控制的,以及这个过程是如何控制的。
有助于T细胞活化。
英文摘要
Interaction of T cells with APCs induces dramatic remodeling of the actin cytoskeleton at the immune
synapse. This process is absolutely required for T cell activation, and severe immunodeficiency or
autoimmune disease result from mutations in actin regulatory molecules like WASP and HS1. This study will
test the central hypothesis that HS1, WIP, and WASP function in a coordinate fashion to orchestrate actin
dynamics at the immune synapse, such that each component plays a distinct role in regulating actin
architecture, while modulating the function of the others. In Aim 1, we will ask to what extent these proteins
interact directly, and seek to place HS1 in the context of the actin regulatory complex involving WIP, WASP,
Itk and Vav. We will ask how these actin regulatory molecules affect one another's stability, targeting and
conformation, and analyze movements of fluorescently tagged proteins in living T cells. In Aim 2, we will
conduct functional analyses during T cell activation using cells lacking individual actin regulatory proteins.
Video analysis of actin dynamics and EM of cortical actin will be performed to test the idea that WASP and
WIP collaborate to drive actin polymerization, while HS1 acts to stabilize actin filaments. In addition, actin-
dependent T cell responses ranging from immune synapse formation to proliferation and cytokine production
will be assessed. In Aim 3, we will conduct structure-function analysis of HS1 by expressing mutants in
HS1-deficient T cells and assaying actin responses and other aspects-of T cell activation. In addition to
testing domains and protein-protein interaction motifs, we will test the function of a lupus-linked insertion
polymorphism. Finally, we will analyze HS1 tyrosine phosphorylation, and test the physiological effects of
non-phosphorylatable point mutants. Taken together, these studies will advance the field toward a molecular
understanding of how actin dynamics at the immune synapse are controlled, and how this process
contributes to T cell activation.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Chemoattractant-specific T cell navigation of complex environments
-
批准号:10741224
-
项目类别:
-
资助金额:$22.25万
-
财政年份:2023
-
负责人:Janis K. Burkhardt
-
依托单位:
Mechanobiology of the immune synapse: signal integration via actin dynamics
-
批准号:10513815
-
项目类别:
-
资助金额:$42.6万
-
财政年份:2020
-
负责人:Janis K. Burkhardt
-
依托单位:
Mechanobiology of the immune synapse: signal integration via actin dynamics
-
批准号:10307597
-
项目类别:
-
资助金额:$42.6万
-
财政年份:2020
-
负责人:Janis K. Burkhardt
-
依托单位:
Modulation of T cell priming by dendritic cell stiffness
-
批准号:9369929
-
项目类别:
-
资助金额:$25.2万
-
财政年份:2017
-
负责人:Janis K. Burkhardt
-
依托单位:
Crosstalk between T cells and inflamed endothelium: regulation by Crk family proteins
-
批准号:9118335
-
项目类别:
-
资助金额:$42.0万
-
财政年份:2015
-
负责人:Janis K. Burkhardt
-
依托单位:
Costimulatory ligand mobility effects on T cell activation
-
批准号:8689121
-
项目类别:
-
资助金额:$33.27万
-
财政年份:2013
-
负责人:Janis K. Burkhardt
-
依托单位:
Costimulatory ligand mobility effects on T cell activation
-
批准号:8841379
-
项目类别:
-
资助金额:$33.27万
-
财政年份:2013
-
负责人:Janis K. Burkhardt
-
依托单位:
Costimulatory ligand mobility effects on T cell activation
-
批准号:8431504
-
项目类别:
-
资助金额:$34.96万
-
财政年份:2013
-
负责人:Janis K. Burkhardt
-
依托单位:
University of Pennsylvania Postdoctoral Opportunities in Research and Teaching
-
批准号:10228016
-
项目类别:
-
资助金额:$114.96万
-
财政年份:2007
-
负责人:Janis K. Burkhardt
-
依托单位:
University of Pennsylvania Postdoctoral Opportunities in Research and Teaching
-
批准号:9981753
-
项目类别:
-
资助金额:$117.58万
-
财政年份:2007
-
负责人:Janis K. Burkhardt
-
依托单位:
Cystoskeletal Remodeling During T Cell Activation
-
批准号:7751259
-
项目类别:
-
资助金额:$39.94万
-
财政年份:2007
-
负责人:Janis K. Burkhardt
-
依托单位:
University of Pennsylvania Postdoctoral Opportunities in Research and Teaching
-
批准号:9751876
-
项目类别:
-
资助金额:$114.96万
-
财政年份:2007
-
负责人:Janis K. Burkhardt
-
依托单位:
IRACDA at the University of Pennsylvania: Penn Postdoctoral Opportunities in Research and Teaching (PennPORT).
-
批准号:10727474
-
项目类别:
-
资助金额:$149.7万
-
财政年份:2007
-
负责人:Janis K. Burkhardt
-
依托单位:
University of Pennsylvania Postdoctoral Opportunities in Research and Teaching
-
批准号:8901192
-
项目类别:
-
资助金额:$92.6万
-
财政年份:2007
-
负责人:Janis K. Burkhardt
-
依托单位:
Cytoskeletal Remodeling During T Cell Activation
-
批准号:7208172
-
项目类别:
-
资助金额:$41.25万
-
财政年份:2007
-
负责人:Janis K. Burkhardt
-
依托单位:
Organization and Function of the Distal Pole Complex During T Cell Activation
-
批准号:7323917
-
项目类别:
-
资助金额:$53.74万
-
财政年份:2007
-
负责人:Janis K. Burkhardt
-
依托单位:
Cystoskeletal Remodeling During T Cell Activation
-
批准号:7545812
-
项目类别:
-
资助金额:$40.34万
-
财政年份:2007
-
负责人:Janis K. Burkhardt
-
依托单位:
Cystoskeletal Remodeling During T Cell Activation
-
批准号:8009793
-
项目类别:
-
资助金额:$39.54万
-
财政年份:2007
-
负责人:Janis K. Burkhardt
-
依托单位:
Organization and Function of the Distal Pole Complex During T Cell Activation
-
批准号:8327645
-
项目类别:
-
资助金额:$58.43万
-
财政年份:2002
-
负责人:Janis K. Burkhardt
-
依托单位:
Organization and Function of the Distal Pole Complex During T Cell Activation
-
批准号:7674721
-
项目类别:
-
资助金额:$57.38万
-
财政年份:2002
-
负责人:Janis K. Burkhardt
-
依托单位:
海外基金