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
基本信息
- 批准号:10392382
- 负责人:
- 金额:$ 52.71万
- 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:2019-08-01 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAnimal ModelAutoantibodiesAutoimmune DiseasesAutoimmunityB-LymphocytesBiopsyCalciumCalcium ChannelCalcium SignalingCalcium ionCell CountCell DeathCell membraneCellsChloride ChannelsChloridesComplexDataDefectDevelopmentDiseaseEpithelial CellsEstrogen ReceptorsEtiologyFemaleFluids and SecretionsFunctional disorderGene DeletionGene ExpressionGenesGeneticGlandGoalsHumanImmuneImmune mediated destructionImmune responseImmune systemImmunityImpairmentInfectionInfiltrationInflammationInflammation MediatorsInflammatoryInnate Immune ResponseInterferonsLacrimal gland structureLeftLinkLymphocyteLymphomaMalignant Lymph Node NeoplasmMediatingMusMutationNatural ImmunityOralPathogenesisPathologyPathway interactionsPatientsPersonsPhenotypePlayPopulationProductionPrognostic MarkerPropertyProteinsReceptor SignalingRegulatory T-LymphocyteRheumatismRoleSTIM1 geneSalivaSalivary GlandsSerumSialadenitisSignal TransductionSjogren&aposs SyndromeStructure of germinal center of lymph nodeSweat GlandsSweatingSymptomsSystemic Lupus ErythematosusT-LymphocyteT-Lymphocyte SubsetsTestingTextTissuesTumor-infiltrating immune cellsVirus DiseasesWaterWomanXerostomiacell typecytokinediagnostic biomarkerdiagnostic criteriaearly detection biomarkerseye drynesshuman diseaseimmune activationimmune functionimmunogenicmouse modelnew therapeutic targetnovelnovel diagnosticspreventresponsetargeted treatmenttool
项目摘要
Project Summary
Sjögren’s syndrome (SjS) is characterized by impaired production of saliva and tears affecting ~1-3 million
people in the US potentially leading to severe complications such as lymphoma. The causes of SjS are
complex and poorly understood. SjS is considered an autoimmune disease in which the body's immune
system turns against itself and causes gland inflammation and destruction. This premise is supported by the
presence of autoantibodies, infiltration of salivary glands by immune cells and increased levels of inflammatory
mediators in most patients. However, whether immune cell infiltration and autoantibodies cause SjS or are the
consequence of gland destruction and/or dysfunction is unknown. Our preliminary data reveal an unexpected
link between SjS and calcium signals in cells of the immune system and salivary glands. Calcium ions within
cells control the function of immune and salivary gland cells. Calcium enters cells through specialized channels
that form pores in the cell's membrane. An important calcium channel in both immune and salivary gland cells
is the CRAC channel, which mediates calcium influx. We found that deletion of genes encoding the CRAC
channel in T cells, a cell type that mediates immunity to infection, abolishes calcium signals and causes SjS-
like disease in mice. This phenotype is even stronger when CRAC channels are deleted in a specific T cell
subset, so-called T regulatory (Treg) cells, that suppresses other immune cells and thereby prevents
autoimmune diseases. These mice develop a disease that recapitulates many features of human SjS. Calcium
signals also control the function of many secretory glands. We recently demonstrated that CRAC channels
regulate sweat production by controlling the function of chloride channels and thus water secretion in sweat
glands cells. Our data further show that mice lacking CRAC channels in salivary glands have impaired saliva
production. This is relevant to SjS as patients can develop dry mouth and eyes before their glands become
inflamed and infiltrated by immune cells, suggesting that altered salivary gland function precedes immune
activation. We hypothesize that impaired calcium signals in salivary gland cells predisposes mice and human
patients to develop SjS by impairing the production of saliva and oral innate immune responses, ultimately
resulting in gland inflammation and immune cell infiltration. The MAIN GOALS of this proposal are to
understand the role of calcium signals in the development and progression of SjS. (1) We will characterize how
calcium influx enables Treg cells to function and prevent the onset of SjS. (2) We will determine how calcium
influx regulates salivary gland function and oral immune responses, thereby preventing SjS. To this end, we
will study two mouse models of SjS that we generated. (3) We will analyze salivary glands and lymphocytes of
human SjS patients for calcium influx and the expression of CRAC channel proteins. The proposed studies will
provide a better understanding of SjS pathology and the role of impaired calcium signals in SjS, which may be
useful as a new diagnostic and prognostic marker for the early detection of SjS.
项目摘要
干燥综合征(SjS)的特征是唾液和眼泪的产生受损,影响约1-3百万人
在美国的人可能导致严重的并发症,如淋巴瘤。SjS的原因是
复杂且不为人知。SjS被认为是一种自身免疫性疾病,
系统会对自身产生反作用,导致腺体炎症和破坏。这一前提得到了
自身抗体的存在,免疫细胞浸润唾液腺和炎症水平增加
在大多数患者中,然而,无论是免疫细胞浸润和自身抗体引起的SjS,
腺体破坏和/或功能障碍的后果尚不清楚。我们的初步数据显示
SjS与免疫系统和唾液腺细胞中钙信号之间的联系。内钙离子
细胞控制免疫和唾液腺细胞的功能。钙通过特殊的通道进入细胞
在细胞膜上形成小孔。免疫和唾液腺细胞中的一种重要钙通道
是CRAC通道,其介导钙内流。我们发现编码CRAC的基因的缺失
T细胞是一种介导对感染的免疫力的细胞类型,它可以消除钙信号并引起SjS-
就像老鼠的疾病一样。当CRAC通道在特定T细胞中缺失时,这种表型甚至更强
T细胞亚群,即所谓的T调节(Treg)细胞,抑制其他免疫细胞,从而防止
自身免疫性疾病这些小鼠发展出一种疾病,重现了人类SjS的许多特征。钙
信号还控制许多分泌腺的功能。我们最近证明了CRAC通道
通过控制氯离子通道的功能来调节汗液的产生,从而调节汗液中的水分分泌
腺细胞我们的数据进一步表明,小鼠唾液腺中缺乏CRAC通道,
生产这与SjS有关,因为患者在腺体变小之前可能会出现口干和眼睛干燥。
炎症和免疫细胞浸润,表明唾液腺功能的改变先于免疫
activation.我们假设唾液腺细胞中受损的钙信号使小鼠和人类
患者通过损害唾液和口腔先天免疫反应的产生而发展SjS,
导致腺体炎症和免疫细胞浸润。本提案的主要目标是
了解钙信号在SjS发生和进展中的作用。(1)我们将描述
钙内流使Treg细胞发挥功能并防止SjS的发作。(2)我们将确定钙
内流调节唾液腺功能和口腔免疫反应,从而预防SjS。为此我们
将研究我们制造的两种SjS小鼠模型。(3)我们将分析唾液腺和淋巴细胞,
人SjS患者的钙内流和CRAC通道蛋白的表达。拟议的研究将
提供了更好的理解SjS病理和受损的钙信号在SjS中的作用,这可能是
作为一种新的诊断和预后标志物,用于早期检测SjS。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
STEFAN FESKE其他文献
STEFAN FESKE的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
$ 52.71万 - 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:
$ 52.71万 - 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:
$ 52.71万 - 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:
$ 52.71万 - 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:
$ 52.71万 - 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:
$ 52.71万 - 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:
$ 52.71万 - 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:
9765152 - 财政年份:2017
- 资助金额:
$ 52.71万 - 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:
$ 52.71万 - 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:
$ 52.71万 - 项目类别:
相似海外基金
Quantification of Neurovasculature Changes in a Post-Hemorrhagic Stroke Animal-Model
出血性中风后动物模型中神经血管变化的量化
- 批准号:
495434 - 财政年份:2023
- 资助金额:
$ 52.71万 - 项目类别:
Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model
用于大型动物模型半月板损伤修复的生物活性可注射细胞支架
- 批准号:
10586596 - 财政年份:2023
- 资助金额:
$ 52.71万 - 项目类别:
A Comparison of Treatment Strategies for Recovery of Swallow and Swallow-Respiratory Coupling Following a Prolonged Liquid Diet in a Young Animal Model
幼年动物模型中长期流质饮食后吞咽恢复和吞咽呼吸耦合治疗策略的比较
- 批准号:
10590479 - 财政年份:2023
- 资助金额:
$ 52.71万 - 项目类别:
Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development
评价唇裂修复疤痕对颅面生长发育影响的小动物模型
- 批准号:
10642519 - 财政年份:2023
- 资助金额:
$ 52.71万 - 项目类别:
Diurnal grass rats as a novel animal model of seasonal affective disorder
昼夜草鼠作为季节性情感障碍的新型动物模型
- 批准号:
23K06011 - 财政年份:2023
- 资助金额:
$ 52.71万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model
自然发生的青光眼动物模型的纵向眼部变化
- 批准号:
10682117 - 财政年份:2023
- 资助金额:
$ 52.71万 - 项目类别:
A whole animal model for investigation of ingested nanoplastic mixtures and effects on genomic integrity and health
用于研究摄入的纳米塑料混合物及其对基因组完整性和健康影响的整体动物模型
- 批准号:
10708517 - 财政年份:2023
- 资助金额:
$ 52.71万 - 项目类别:
A Novel Large Animal Model for Studying the Developmental Potential and Function of LGR5 Stem Cells in Vivo and in Vitro
用于研究 LGR5 干细胞体内外发育潜力和功能的新型大型动物模型
- 批准号:
10575566 - 财政年份:2023
- 资助金额:
$ 52.71万 - 项目类别:
Elucidating the pathogenesis of a novel animal model mimicking chronic entrapment neuropathy
阐明模拟慢性卡压性神经病的新型动物模型的发病机制
- 批准号:
23K15696 - 财政年份:2023
- 资助金额:
$ 52.71万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
The effect of anti-oxidant on swallowing function in an animal model of dysphagia
抗氧化剂对吞咽困难动物模型吞咽功能的影响
- 批准号:
23K15867 - 财政年份:2023
- 资助金额:
$ 52.71万 - 项目类别:
Grant-in-Aid for Early-Career Scientists