Crosstalk between FceRI and MAVS signaling pathways in mast cells
肥大细胞中 FceRI 和 MAVS 信号通路之间的串扰
基本信息
- 批准号:10040848
- 负责人:
- 金额:$ 27.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-22 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdaptor Signaling ProteinAffinityAllergensAllergic DiseaseAllergic ReactionAntigensAntiviral AgentsAsthmaBasophilsBindingCell DensityCellsCytokine GeneCytoplasmDataDisulfidesDouble-Stranded RNAEicosanoidsEnzymesEventFamilyGenesGenetic TranscriptionGenetically Engineered MouseHealth Care CostsHistamine ProductionHistamine ReleaseIRF3 geneITAMIgEIgE ReceptorsIn VitroInfectionInflammatoryInfluenza A virusInterferon Type IInterleukin-13Interleukin-4LCP2 geneLigandsLinkLung InflammationMAP Kinase GeneMast Cell StabilizerMediatingMediator of activation proteinMitochondriaMolecularMorbidity - disease rateMusNF-kappa BOuter Mitochondrial MembranePTPN6 genePassive Cutaneous AnaphylaxisPathogenesisPathway interactionsPatientsPattern recognition receptorPeptide HydrolasesPharmacologyPhasePhosphoric Monoester HydrolasesPhosphorylationPlayPrevalencePrevention strategyPreventivePreventive InterventionProductionProstaglandinsProtein FamilyProtein Tyrosine KinaseProtein Tyrosine PhosphatasePulmonary PathologyRNARNA HelicaseRNA VirusesReceptor SignalingRegulationRespiratory SystemRoleSignal PathwaySignal TransductionSignaling MoleculeSignaling ProteinStructureT-LymphocyteTBK1 geneTLR3 geneTLR7 geneTNF geneTherapeuticToll-like receptorsTranscriptional ActivationTretinoinTyrosineTyrosine PhosphorylationUbiquitinVirus Diseasesactivating transcription factorasthma exacerbationbasechemokinecrosslinkcysteinyl-leukotrienecytokineexperimental studyi(19)in vivoinfluenzavirusinnovationinsightmast cellmelanomamortalitynovelnovel therapeuticspathogenphospholipase C gammapreventprion-likereceptorrecruitrespiratory infection virusrespiratory virusresponsesrc Homology Region 2 Domainsrc-Family Kinasestranscription factor
项目摘要
Project Summary
The prevalence of asthma and allergic diseases has been increasing for the last several decades. IgE plays a
central role for the pathogenesis of asthma and allergic diseases. IL-4 and IL-13 stimulate the production of
IgE. Multivalent allergen induces the cross-linking of IgE-bound high-affinity IgE receptors (FceRI) on mast
cells and basophils. Cross-linking of FceRI initiates activation of several protein-tyrosine kinases (PTKs)
including receptor-associated Lyn and other Src PTKs, which phosphorylate tyrosine residues of the
immunoreceptor tyrosine-based activation motifs (ITAMs) in signaling subunits of the receptor." Tyrosine-
phosphorylated g subunits recruit Syk, the PTK essential for triggering downstream activation events (i.e.,
degranulation of preformed allergenic mediators and de novo synthesis and secretion of eicosanoids and
various cytokines and chemokines), eventually leading to the initiation of allergic reactions.
Respiratory virus infection-induced acute exacerbations of asthma represent severe morbidity, mortality,
and burdensome healthcare costs. Host cells infected with influenza A virus (IAV) sense the infection by
pattern recognition receptors such as RIG-I. Signaling by RIG-I-like receptors (RLRs) occurs through the
adaptor mitochondrial antiviral-signaling protein (MAVS) at the outer membrane of the mitochondria. Once
activated, MAVS in turn activates TBK1 and IKKe, leading to phosphorylation and activation of the transcription
factors IRF3/IRF7 and NF-kB. IRF3 and IRF7 activate the transcription of type I interferon (IFN) genes while
NF-kB activates that of inflammatory cytokine genes. Mast cells are also implicated in virus infections. Mast
cell production of cytokines and chemokines during IAV infection occurs in a RIG-I/MAVS-dependent
mechanism, whereas histamine production occurs through a RIG-I/MAVS-independent mechanism. Mast cell-
deficient mice and ketotifen (mast cell stabilizer)-treated mice showed reduced IAV-induced lung pathology
compared to mast cell-sufficient mice and untreated mice, respectively. Therefore, it is likely that mast cells
contribute to asthma exacerbations via the crosstalk between FceRI and antiviral signaling pathways.
Our preliminary data demonstrates that MAVS, among the signaling molecules of RLR antiviral pathways,
uniquely and strongly inhibits Syk activity in antigen/IgE-induced mast cell activation. Thus, Syk may be
negatively regulated by a Syk- and/or MAVS-associated tyrosine phosphatase(s). In Aim 1, we will investigate
whether Syk is regulated by TULA-2 or SHP-1/2 in a MAVS-dependent manner. These candidate
phosphatases will be intensively analyzed for this possibility. In Aim 2, we will investigate the in vivo and in
vitro roles of mast cell-expressed MAVS and Syk in IAV infection. Therefore, through this project, we will gain
mechanistic insights into how Syk is regulated by MAVS in mast cells and how the crosstalk between FceRI
and antiviral RLR signaling pathways impacts IAV infection. Such information will be basis for novel
therapeutic/preventive interventions of IAV-induced asthma exacerbations.
项目总结
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 }}
TOSHIAKI KAWAKAMI其他文献
TOSHIAKI KAWAKAMI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('TOSHIAKI KAWAKAMI', 18)}}的其他基金
Histamine-Releasing Factor Oligomers in Food Allergy
食物过敏中的组胺释放因子低聚物
- 批准号:
10462489 - 财政年份:2019
- 资助金额:
$ 27.45万 - 项目类别:
Histamine-Releasing Factor Oligomers in Food Allergy
食物过敏中的组胺释放因子低聚物
- 批准号:
10212221 - 财政年份:2019
- 资助金额:
$ 27.45万 - 项目类别:
Interaction of histamine-releasing factor with immunoglobulins in asthma
哮喘中组胺释放因子与免疫球蛋白的相互作用
- 批准号:
8766032 - 财政年份:2014
- 资助金额:
$ 27.45万 - 项目类别:
Mast cell Stat5-regulatory pathway in atopic dermatitis
特应性皮炎中肥大细胞 Stat5 调节通路
- 批准号:
9042923 - 财政年份:2014
- 资助金额:
$ 27.45万 - 项目类别:
Interaction of histamine-releasing factor with immunoglobulins in asthma
哮喘中组胺释放因子与免疫球蛋白的相互作用
- 批准号:
9298705 - 财政年份:2014
- 资助金额:
$ 27.45万 - 项目类别:
Regulation of asthma by Btk and family kinases
Btk 和家族激酶对哮喘的调节
- 批准号:
6831364 - 财政年份:2004
- 资助金额:
$ 27.45万 - 项目类别:
Regulation of asthma by Btk and family kinases
Btk 和家族激酶对哮喘的调节
- 批准号:
7083557 - 财政年份:2004
- 资助金额:
$ 27.45万 - 项目类别:
Regulation of asthma by Btk and family kinases
Btk 和家族激酶对哮喘的调节
- 批准号:
7248798 - 财政年份:2004
- 资助金额:
$ 27.45万 - 项目类别:
Regulation of asthma by Btk and family kinases
Btk 和家族激酶对哮喘的调节
- 批准号:
6919293 - 财政年份:2004
- 资助金额:
$ 27.45万 - 项目类别:
Regulation of asthma by Btk and family kinases
Btk 和家族激酶对哮喘的调节
- 批准号:
7470157 - 财政年份:2004
- 资助金额:
$ 27.45万 - 项目类别:














{{item.name}}会员




