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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.

项目总结/文摘