Regulation of Follicular T cell Responses in the Lung by Ion Channels
离子通道对肺滤泡 T 细胞反应的调节
基本信息
- 批准号:9765152
- 负责人:
- 金额:$ 47.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-25 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:ATAC-seqAddressAffectAntibodiesAntibody FormationAntiviral AgentsAttenuatedB-LymphocytesBindingBiologicalBiological Response ModifiersCD4 Positive T LymphocytesCRISPR/Cas technologyCalciumCalcium ChannelCell Differentiation processCell membraneCell physiologyCellsCellular ImmunityCessation of lifeChIP-seqChromatinCustomDataDefectDevelopmentEndoplasmic ReticulumEventGene DeletionGene ExpressionGenerationsGenesGenetic TranscriptionGoalsHealthHelper-Inducer T-LymphocyteHumanHumoral ImmunitiesImmune responseImmunityImmunoglobulin AImmunoglobulin Class SwitchingImmunoglobulin GImmunologic Deficiency SyndromesImpairmentIncidenceInfectionInfluenzaInfluenza A virusInfluenza vaccinationIon ChannelIonsKnowledgeLibrariesLifeLungLung infectionsLymphocytic choriomeningitis virusMammalsMature B-LymphocyteMediatingMembrane ProteinsMemory B-LymphocyteMolecularMonoclonal AntibodiesMusMutationNaturePathway interactionsPatientsPlasma CellsPlayPrimary InfectionProductionProteinsRecurrenceRegulationRiskRoleSTIM1 geneSeveritiesShapesStructure of germinal center of lymph nodeT cell responseT-Cell ReceptorT-LymphocyteTestingTherapeuticVaccinatedVaccinationVirusVirus Diseasesadaptive immunityantiviral immunitycell mediated immune responsehuman pathogenin vivoinfluenzavirusinsightneutralizing antibodynext generation sequencingnovelpathogenresponsescreeningsmall hairpin RNAsmall molecule inhibitortargeted treatmenttranscription factortranscriptome sequencingwhole genome
项目摘要
Project Summary
The overall goal of this application is to understand how ion channels in T cells regulate immune responses to
pulmonary infection with influenza virus. Influenza is major health risk and affect millions of patients in the US
and worldwide. CD4 T cells play a critical role in supporting germinal center B cells to produce neutralizing
antibodies against influenza virus and to become memory B cells, which together provide immunity against
reinfection. The function of CD4 T cells is regulated by ion channels that mediate the influx of calcium and
other ions. The calcium release-activated calcium (CRAC) channel, which is formed by ORAI1 proteins in the
plasma membrane, is one of the best characterized channels in T cells. It mediates a specific and essential
form of calcium influx, store-operated Ca2+ entry (SOCE), so called because it is triggered by the release of
calcium from the endoplasmic reticulum. Ca2+ release activates stromal interaction molecule 1 (STIM1) and
STIM2 and results in the opening of ORAI1 CRAC channels. Mutations in ORAI1 or STIM1 genes in human
patients that abolish SOCE cause immunodeficiency with recurrent infections due to impaired T cell function
and production of pathogen-specific antibodies. This defect is mimicked by STIM1/STIM2 double-deficient
mice, whose CD4 T cells fail to develop into follicular T helper (TFH) cells and to help B cells mature into
germinal center B cells after viral infection. We found that mice lacking STIM1/STIM2 in T cells cannot produce
virus-specific antibodies upon infection with lymphocytic choriomeningitis virus (LCMV) or vaccination with
influenza virus. Important goals of this application are to understand whether CRAC channels in TFH cells
control pulmonary immune responses to infection with influenza and to characterize the molecular mechanisms
by which CRAC channels control the development and function of TFH cells in influenza. Besides the CRAC
channel, about 600 ion channels and transporters are expressed in mammals, but to date only a few are
established to contribute to T cell-mediated immune responses. We hypothesize that other ion channels
besides the CRAC channel play important roles in regulating TFH cell-dependent humoral immunity to
influenza. However, no studies have systematically addressed this question so far, which is a major gap in our
knowledge of T cell physiology and adaptive immunity. We will address this gap and systematically screen for
and characterize ion channels that regulate TFH cell-dependent humoral immune responses to influenza in
vivo. The long-term goal of our study is to identify ion channels and downstream molecules they regulate that
can be targeted therapeutically to enhance humoral immunity to influenza infection and vaccination. Since
many ion channels are plasma membrane proteins, they are accessible to small molecule inhibitors or
biologicals such as monoclonal antibodies to modulate their function and immune responses to influenza.
项目摘要
本申请的总体目标是了解T细胞中的离子通道如何调节免疫应答,
流感病毒肺部感染。流感是主要的健康风险,影响美国数百万患者
和世界各地。CD 4 T细胞在支持生殖中心B细胞产生中和性T细胞中起关键作用。
抗体,并成为记忆B细胞,它们一起提供免疫力,
再感染CD 4 T细胞的功能由离子通道调节,离子通道介导钙离子的流入,
其他离子钙释放激活的钙通道(CRAC),是由视网膜中的ORAI 1蛋白形成的。
质膜是T细胞中最具特征的通道之一。它调节了一个特定的和必要的
钙内流的一种形式,即钙库操纵的钙内流(SOCE),之所以这么叫是因为它是由释放
从内质网中获取钙。Ca 2+释放激活基质相互作用分子1(STIM 1),
STIM 2,并导致打开ORAI 1 CRAC通道。人的ORAI 1或STIM 1基因突变
废除SOCE的患者由于T细胞功能受损而导致免疫缺陷和复发性感染
和病原体特异性抗体的产生。该缺陷由STIM 1/STIM 2双缺陷模拟
小鼠,其CD 4 T细胞不能发育成滤泡性T辅助(TFH)细胞,也不能帮助B细胞成熟为
生殖中心B细胞。我们发现T细胞中缺乏STIM 1/STIM 2的小鼠不能产生
感染淋巴细胞性脉络丛脑膜炎病毒(LCMV)或接种
流感病毒。本申请的重要目标是了解TFH细胞中的CRAC通道是否
控制肺部对流感感染的免疫反应,并描述其分子机制
CRAC通道通过其控制流感中TFH细胞的发育和功能。除了CRAC
通道,哺乳动物中表达约600种离子通道和转运蛋白,但迄今为止只有少数
建立有助于T细胞介导的免疫应答。我们假设其他离子通道
此外,CRAC通道在调节TFH细胞依赖的体液免疫中起重要作用,
流感。然而,到目前为止,还没有研究系统地解决这个问题,这是我们研究的一个主要空白。
了解T细胞生理学和适应性免疫。我们将解决这一差距,并系统地筛选
并表征了调节TFH细胞依赖的对流感的体液免疫应答的离子通道,
vivo.我们研究的长期目标是确定离子通道和它们调节的下游分子,
可以在治疗上靶向增强对流感感染和疫苗接种的体液免疫。以来
许多离子通道是质膜蛋白,它们可被小分子抑制剂或
生物制剂如单克隆抗体来调节它们的功能和对流感的免疫应答。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('STEFAN FESKE', 18)}}的其他基金
Ca2+ signaling via SOCE in the pathogenesis of Sjögren’s syndrome
干燥综合征发病机制中通过 SOCE 的 Ca2 信号传导
- 批准号:
10153457 - 财政年份:2019
- 资助金额:
$ 47.46万 - 项目类别:
Ca2+ signaling via SOCE in the pathogenesis of Sjögren’s syndrome
干燥综合征发病机制中通过 SOCE 的 Ca2 信号传导
- 批准号:
9980846 - 财政年份:2019
- 资助金额:
$ 47.46万 - 项目类别:
Ca2+ signaling via SOCE in the pathogenesis of Sjögren’s syndrome
干燥综合征发病机制中通过 SOCE 的 Ca2 信号传导
- 批准号:
10626980 - 财政年份:2019
- 资助金额:
$ 47.46万 - 项目类别:
Ca2+ signaling via SOCE in the pathogenesis of Sjögren’s syndrome
干燥综合征发病机制中通过 SOCE 的 Ca2 信号传导
- 批准号:
10392382 - 财政年份:2019
- 资助金额:
$ 47.46万 - 项目类别:
Calcium channel CACNB1 in T cell function and immunity
钙通道 CACNB1 在 T 细胞功能和免疫中的作用
- 批准号:
9811165 - 财政年份:2019
- 资助金额:
$ 47.46万 - 项目类别:
Regulation of encephalitogenic T cells by CRAC channels
CRAC 通道对致脑炎 T 细胞的调节
- 批准号:
10461826 - 财政年份:2018
- 资助金额:
$ 47.46万 - 项目类别:
Regulation of encephalitogenic T cells by CRAC channels
CRAC 通道对致脑炎 T 细胞的调节
- 批准号:
9981624 - 财政年份:2018
- 资助金额:
$ 47.46万 - 项目类别:
Regulation of encephalitogenic T cells by CRAC channels
CRAC 通道对致脑炎 T 细胞的调节
- 批准号:
10238856 - 财政年份:2018
- 资助金额:
$ 47.46万 - 项目类别:
Regulation of Follicular T cell Responses in the Lung by Ion Channels
离子通道对肺滤泡 T 细胞反应的调节
- 批准号:
9444252 - 财政年份:2017
- 资助金额:
$ 47.46万 - 项目类别:
Identifying Novel Ion Channels Regulating T cell Function
识别调节 T 细胞功能的新型离子通道
- 批准号:
9297218 - 财政年份:2016
- 资助金额:
$ 47.46万 - 项目类别:
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