Cytosolic DNA sensing pathway in the pathogenesis of Sjogren's Syndrome
干燥综合征发病机制中的细胞质 DNA 传感途径
基本信息
- 批准号:10265571
- 负责人:
- 金额:$ 21.85万
- 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:2020-09-17 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAdverse effectsAffectAgeAgingAreaAutoimmune DiseasesBindingCannulationsCell AgingCell NucleusCellsCharacteristicsChronicClinicalComplementCultured CellsCyclic GMPCytosolDNADataDevelopmentDiagnosisDiseaseDrug TargetingEnterobacteria phage P1 Cre recombinaseEpithelial CellsExocrine GlandsExtravasationFatigueGastrointestinal tract structureGene ActivationGene ExpressionGene ProteinsGenesGenetic TranscriptionGoalsGolgi ApparatusIL6 geneIRF3 geneImmune TargetingImmune responseIn VitroInflammatoryInflammatory ResponseInnate Immune ResponseInterferon Type IInterferonsJointsKnockout MiceLeadLinkLiteratureLoxP-flanked alleleLungManganeseMediatingMitochondriaMitochondrial DNAModelingMonitorMusMutant Strains MiceNF-kappa BNatural ImmunityNervous system structureNucleotidesOxidative StressPathogenesisPathogenicityPathway interactionsPatientsPlayProcessProductionProtein-Serine-Threonine KinasesProteinsPublishingResearchRoleSalivarySalivary GlandsSeverity of illnessSjogren&aposs SyndromeStimulator of Interferon GenesSubmandibular glandSuperoxide DismutaseTBK1 geneTNF geneTamoxifenTargeted ResearchTestingTherapeuticTherapeutic InterventionXerostomiaadeno-associated viral vectorbasebody systemchemokineconditional knockoutconditional mutantcytokinedrug testingeye drynessfactor Ahuman old age (65+)in vivolacrimalmitochondrial dysfunctionmouse modelnovelprotein expressionresponsesenescencesensorstressortargeted treatmenttranscription factor
项目摘要
Sjögren’s syndrome (SS) is a chronic, autoimmune disorder affecting almost all organ
systems, including the exocrine glands, nervous system, joints, lungs, and the gastrointestinal
tract. It is widely accepted that SS pathogenesis is associated with excessive activation of innate
immunity and type I interferon (IFN) production, but the precise mechanisms for initiating and
sustaining these responses in SS remain unknown. Recent studies have established that DNA
released from damaged or dysfunctional mitochondria can lead to type I IFN production
through the activation of cytosolic DNA sensing pathways. The stimulator of interferon gene
(STING) protein is a central component of these pathways. Our published study has established
that systemic activation of the STING pathway induces SS-like disease in mice. Our preliminary
studies show that the STING pathway is functional in salivary gland epithelial cells, and its
activation induces a robust type I IFN response.
The present proposal tests the overall hypothesis that mitochondrial DNA (mtDNA)
mediated activation of the STING pathway in salivary gland cells influences the pathogenesis of
SS. We will test this hypothesis in vitro using salivary gland cells cultured from mouse
submandibular glands, and we will complement these studies in vivo, by developing novel
mouse models for mitochondrial damage in salivary glands. In Aim 1, we will define pathways
involved in mtDNA mediated activation of STING in salivary gland cells, and investigate
whether STING activation induces senescence. In Aim 2, we will investigate the in vivo effects of
mitochondrial damage and STING activation on salivary glands. For this purpose, we will
generate salivary gland conditional mutant mice for the transcription factor A, mitochondrial
(Tfam), and Manganese dependent Superoxide dismutase (Sod2).
In the context of SS, mitochondrial damage and innate immunity activation within the
salivary glands is an underexplored area. The findings from this proposal will facilitate research
targeting the role of oxidative stress and aging, known causes of mitochondrial damage, in SS
pathogenesis, and provide possible targets for therapeutic interventions.
Sjögren综合征(SS)是一种影响几乎所有器官的慢性自身免疫性疾病
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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Umesh S Deshmukh其他文献
Umesh S Deshmukh的其他文献
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{{ truncateString('Umesh S Deshmukh', 18)}}的其他基金
Aging and Oxidative Stress Influence Salivary Gland Disease in Sjogren's Syndrome
衰老和氧化应激对干燥综合征唾液腺疾病的影响
- 批准号:
10682148 - 财政年份:2023
- 资助金额:
$ 21.85万 - 项目类别:
Salivary gland response to innate immune mediators dictates Sjogren's syndrome development
唾液腺对先天免疫介质的反应决定了干燥综合征的发展
- 批准号:
10432111 - 财政年份:2021
- 资助金额:
$ 21.85万 - 项目类别:
Salivary gland response to innate immune mediators dictates Sjogren's syndrome development
唾液腺对先天免疫介质的反应决定了干燥综合征的发展
- 批准号:
10317601 - 财政年份:2021
- 资助金额:
$ 21.85万 - 项目类别:
Innate immunity and autoantibodies in the pathogenesis of Sjogren's Syndrome
干燥综合征发病机制中的先天免疫和自身抗体
- 批准号:
9340332 - 财政年份:2015
- 资助金额:
$ 21.85万 - 项目类别:
Adenosine Receptors and Restoration of Salivary Gland in Sjogren's Syndrome
腺苷受体与干燥综合征唾液腺的恢复
- 批准号:
8390609 - 财政年份:2012
- 资助金额:
$ 21.85万 - 项目类别:
Adenosine Receptors and Restoration of Salivary Gland in Sjogren's Syndrome
腺苷受体与干燥综合征唾液腺的恢复
- 批准号:
8508243 - 财政年份:2012
- 资助金额:
$ 21.85万 - 项目类别:
Innate Immunity Activation In Pathogenesis of Sjogren's Syndrome
干燥综合征发病机制中的先天免疫激活
- 批准号:
8064723 - 财政年份:2010
- 资助金额:
$ 21.85万 - 项目类别:
Innate Immunity Activation In Pathogenesis of Sjogren's Syndrome
干燥综合征发病机制中的先天免疫激活
- 批准号:
7896758 - 财政年份:2010
- 资助金额:
$ 21.85万 - 项目类别:
T Cell Epitope Mimicry for Autoimmune Responses in SLE
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8291356 - 财政年份:2009
- 资助金额:
$ 21.85万 - 项目类别:
T Cell Epitope Mimicry for Autoimmune Responses in SLE
T 细胞表位模拟对 SLE 自身免疫反应的影响
- 批准号:
8089292 - 财政年份:2009
- 资助金额:
$ 21.85万 - 项目类别:
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