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:9286500
- 负责人:
- 金额:$ 38万
- 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:Adverse effectsAntigensAssessment toolAutoantigensAutoimmune ProcessAutoimmunityB-LymphocytesBindingBiochemicalBiological AssayBiopsy SpecimenCell DeathCell physiologyCellsComplexDevelopmentDiseaseFatty acid glycerol estersFoundationsFunctional ImagingFunctional disorderGeneral PopulationGenetic TranscriptionHand StrengthHistidine-tRNA LigaseHistologicHumanIdiopathic Inflammatory MyopathiesImmuneImmune TargetingImmune signalingImmunizationImmunizeImpairmentIn VitroInfiltrationInflammationInflammatoryInjuryInnate Immune ResponseInterleukin-1IntramuscularIschemiaKnock-outKnockout MiceLaboratoriesLinkLuciferasesLymphocyteMagnetic Resonance ImagingMediatingModelingMolecularMorbidity - disease rateMusMuscleMuscle CellsMuscle WeaknessMuscular DystrophiesMyoblastsMyopathyMyositisNatural ImmunityOrganPathogenesisPathogenicityPathologicPathologyPathway interactionsPeptidesPhenotypePlayProcessProductionProteinsReceptor SignalingRecombinantsRecruitment ActivityRoleSecondary 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 signalingregenerativesystemic 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.
项目概要/摘要
特发性炎症性肌病(IIM)代表一组系统性自身免疫性疾病,其中
肌肉和肌外器官是免疫介导破坏的目标。我们之前有过
建立了组氨酰-tRNA 合成酶 (HRS) 诱导的肌炎模型,该模型涉及 MyD88 依赖性
以 Toll 样受体 2 和 4(TLR2、TLR4)为特征的先天免疫信号传导通路。鉴于突出的
这些 TLR 在我们的 HRS 诱发的肌炎模型中的作用,我们假设增强的 TLR 激活
下游转录调节因子 NF-κB 也最终负责各种炎症级联反应
作为促进该系统中肌肉功能障碍的非免疫途径——有效地将 HRS 诱导的
肌炎/IIM 合并其他疾病(包括肌营养不良以及败血症和创伤/缺血)
诱发性肌病),其中 NF-κB 失调会导致肌肉炎症、肌肉退化、
和再生潜力受损。通过一系列的体外培养系统和体内免疫
涉及缺乏 MyD88 依赖性信号通路关键成分的基因敲除小鼠的策略,我们
将系统地研究 HRS 诱导的 TLR 信号传导和 NF-κB 激活对 T 细胞迁移的影响,
T 细胞激活和肌肉无力。具体目标 1 将重点关注 HRS 诱导的 T 细胞变化
功能和 TLR 介导的血管内皮激活(导致靶标淋巴细胞浸润)
器官),具体目标 2 将定义 HRS 诱导肌肉中 NF-κB 激活的直接和间接途径
通过体外成肌细胞刺激测定以及其他免疫研究重点关注组织
肌肉炎症、NF-κB 激活和肌肉体内/离体参数之间的相关性
弱点。补充体内评估工具,包括 MRI 和 NF-κB-荧光素酶转基因的使用
小鼠将进一步明确 HRS 介导的 NF-κB 激活与肌肉功能障碍之间的关系,
为特定目标 3 中比较 NF-κB 抑制的实验试验提供基础。总的来说,
这些研究将阐明先天免疫对 IIM 发病机制的贡献,补充更多
抗原特异性、适应性免疫识别和识别治疗靶标的传统范例
可能与一系列人类炎症性肌肉疾病相关。
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('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:
10532784 - 财政年份:2021
- 资助金额:
$ 38万 - 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:
10362978 - 财政年份:2021
- 资助金额:
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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:
$ 38万 - 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
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$ 38万 - 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:
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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
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8696779 - 财政年份:2011
- 资助金额:
$ 38万 - 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:
$ 38万 - 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:
$ 38万 - 项目类别:
Functional impact of dendritic cell phenotype in a mouse model of myositis
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