Innate Immune Activation in Autoimmune Myopathy
自身免疫性肌病的先天免疫激活
基本信息
- 批准号:9926715
- 负责人:
- 金额:$ 39.39万
- 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:2017-04-10 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:AntigensAssessment toolAutoantigensAutoimmune ProcessAutoimmunityB-LymphocytesBindingBiochemicalBiological AssayBiopsy SpecimenCell DeathCell physiologyCellsComplexDevelopmentDiseaseFatty acid glycerol estersFoundationsFunctional ImagingFunctional disorderGeneral PopulationGenetic TranscriptionHand StrengthHistidine-tRNA LigaseHistologicHumanIdiopathic Inflammatory MyopathiesImmuneImmune TargetingImmune signalingImmunizationImmunizeImpairmentIn VitroInfiltrationInflammationInflammatoryInjuryInnate Immune ResponseInterleukin-1 betaIntramuscularIschemiaKnock-outKnockout MiceLaboratoriesLinkLuciferasesLymphocyteMagnetic Resonance ImagingMediatingModelingMolecularMorbidity - disease rateMusMuscleMuscle CellsMuscle WeaknessMuscular DystrophiesMyoblastsMyopathyMyositisNatural ImmunityOrganPathogenesisPathogenicityPathologicPathologyPathway interactionsPeptidesPhenotypePlayProcessProductionProteinsReceptor SignalingRecombinantsRoleSecondary toSepsisSeriesSignal PathwaySignal TransductionSystemT-Cell ActivationT-Cell ReceptorT-LymphocyteTLR2 geneTLR4 geneTNF geneTherapeuticTherapeutic AgentsTherapeutic immunosuppressionTissuesToll-like receptorsTransgenic MiceTraumaTreatment EfficacyTumor Necrosis Factor ReceptorVascular EndotheliumWorkadaptive immune responsebasecell motilitycomparative trialcytokinehuman diseaseimmune activationin vivoinsightmortalitymuscle degenerationmyogenesisnovel therapeuticspreventreceptor-mediated signalingrecruitregenerativeside effectsystemic autoimmune diseasetargeted treatmenttherapeutic targettooltraffickingtranscription factor
项目摘要
PROJECT SUMMARY/ABSTRACT
The idiopathic inflammatory myopathies (IIMs) represent a group of systemic autoimmune disorders in which
muscle and extra-muscular organs are targeted for immune-mediated destruction. We have previously
established a model of histidyl-tRNA synthetase (HRS)-induced myositis that involves MyD88-dependent
innate immune signaling pathways featuring Toll-like receptors 2 and 4 (TLR2, TLR4). Given the prominent
role of these TLRs in our model of HRS-induced myositis, we hypothesize that heightened activation of the
downstream transcription regulator NF-κB is ultimately responsible for various inflammatory cascades as well
as non-immune pathways promoting muscle dysfunction in this system—effectively linking HRS-induced
myositis/IIM with other disorders (including muscular dystrophy as well as sepsis- and trauma/ischemia-
induced myopathies) in which NF-κB dysregulation contributes to muscle inflammation, muscle degeneration,
and impaired regenerative potential. Through a series of in vitro culture systems and in vivo immunization
strategies involving knockout mice lacking critical components of MyD88-dependent signaling pathways, we
will systematically examine the impact of HRS-induced TLR signaling and NF-κB activation on T cell migration,
T cell activation, and muscle weakness. While Specific Aim 1 will focus on HRS-induced changes in T cell
function and TLR-mediated activation of vascular endothelium (leading to lymphocytic infiltration of target
organs), Specific Aim 2 will define direct and indirect pathways of HRS-induced NF-κB activation in muscle
tissue through in vitro myoblast stimulation assays as well as additional immunization studies focusing on
correlations between muscle inflammation, NF-κB activation, and in vivo/ex vivo parameters of muscle
weakness. Complementary in vivo assessment tools including MRI and the use of NF-κB-luciferase transgenic
mice will further define the relationship between HRS-mediated NF-κB activation and muscle dysfunction,
providing the foundation for experimental trials of comparative NF-κB inhibition in Specific Aim 3. Collectively,
these studies will elucidate the contribution of innate immunity to the pathogenesis of IIM, supplementing more
traditional paradigms of antigen-specific, adaptive immune recognition and identifying therapeutic targets that
are potentially relevant to a range of human inflammatory muscle diseases.
项目总结/文摘
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)
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DANA P ASCHERMAN其他文献
DANA P ASCHERMAN的其他文献
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{{ truncateString('DANA P ASCHERMAN', 18)}}的其他基金
Evaluating Clinical and Immunological Consequences of SARS-CoV-2 Vaccination in Rheumatic Disease
评估风湿性疾病中 SARS-CoV-2 疫苗接种的临床和免疫学后果
- 批准号:
10362978 - 财政年份:2021
- 资助金额:
$ 39.39万 - 项目类别:
Evaluating Clinical and Immunological Consequences of SARS-CoV-2 Vaccination in Rheumatic Disease
评估风湿性疾病中 SARS-CoV-2 疫苗接种的临床和免疫学后果
- 批准号:
10532784 - 财政年份:2021
- 资助金额:
$ 39.39万 - 项目类别:
Innate Immune Activation in Autoimmune Myopathy
自身免疫性肌病的先天免疫激活
- 批准号:
9286500 - 财政年份:2017
- 资助金额:
$ 39.39万 - 项目类别:
Peripheral Blood Biomarkers of RA-associated Interstitial Lung Disease
RA 相关间质性肺病的外周血生物标志物
- 批准号:
8278446 - 财政年份:2011
- 资助金额:
$ 39.39万 - 项目类别:
Peripheral Blood Biomarkers of RA-associated Interstitial Lung Disease
RA 相关间质性肺病的外周血生物标志物
- 批准号:
8397571 - 财政年份:2011
- 资助金额:
$ 39.39万 - 项目类别:
Peripheral Blood Biomarkers of RA-associated Interstitial Lung Disease
RA 相关间质性肺病的外周血生物标志物
- 批准号:
8696779 - 财政年份:2011
- 资助金额:
$ 39.39万 - 项目类别:
Peripheral Blood Biomarkers of RA-associated Interstitial Lung Disease
RA 相关间质性肺病的外周血生物标志物
- 批准号:
8142414 - 财政年份:2011
- 资助金额:
$ 39.39万 - 项目类别:
Functional impact of dendritic cell phenotype in a mouse model of myositis
树突状细胞表型对肌炎小鼠模型的功能影响
- 批准号:
7659076 - 财政年份:2009
- 资助金额:
$ 39.39万 - 项目类别:
Functional impact of dendritic cell phenotype in a mouse model of myositis
树突状细胞表型对肌炎小鼠模型的功能影响
- 批准号:
8188933 - 财政年份:2009
- 资助金额:
$ 39.39万 - 项目类别:
Functional impact of dendritic cell phenotype in a mouse model of myositis
树突状细胞表型对肌炎小鼠模型的功能影响
- 批准号:
7799180 - 财政年份:2009
- 资助金额:
$ 39.39万 - 项目类别:
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