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：
DANA P ASCHERMAN
金额：
$ 39.39万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
https://reporter.nih.gov/project-details/9926715
关键词：
Antigens Assessment tool Autoantigens Autoimmune Process Autoimmunity B-Lymphocytes Binding Biochemical Biological Assay Biopsy Specimen Cell Death Cell physiology Cells Complex Development Disease Fatty acid glycerol esters Foundations Functional Imaging Functional disorder General Population Genetic Transcription Hand Strength Histidine-tRNA Ligase Histologic Human Idiopathic Inflammatory Myopathies Immune Immune Targeting Immune signaling Immunization Immunize Impairment In Vitro Infiltration Inflammation Inflammatory Injury Innate Immune Response Interleukin-1 beta Intramuscular Ischemia Knock-out Knockout Mice Laboratories Link Luciferases Lymphocyte Magnetic Resonance Imaging Mediating Modeling Molecular Morbidity - disease rate Mus Muscle Muscle Cells Muscle Weakness Muscular Dystrophies Myoblasts Myopathy Myositis Natural Immunity Organ Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Peptides Phenotype Play Process Production Proteins Receptor Signaling Recombinants Role Secondary to Sepsis Series Signal Pathway Signal Transduction System T-Cell Activation T-Cell Receptor T-Lymphocyte TLR2 gene TLR4 gene TNF gene Therapeutic Therapeutic Agents Therapeutic immunosuppression Tissues Toll-like receptors Transgenic Mice Trauma Treatment Efficacy Tumor Necrosis Factor Receptor Vascular Endothelium Work adaptive immune response base cell motility comparative trial cytokine human disease immune activation in vivo insight mortality muscle degeneration myogenesis novel therapeutics prevent receptor-mediated signaling recruit regenerative side effect systemic autoimmune disease targeted treatment therapeutic target tool trafficking transcription 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。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通路。这些 TLR 在我们的 HRS 诱发的肌炎模型中的作用，我们捕获了哮喘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、和受损的再生潜力。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，而具体目标 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）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，补充更多信息抗原特异性、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。