Cell Membrane Resealing in Inflammatory Myopathy

炎症性肌病中的细胞膜重新密封

• 批准号: 10708321
• 负责人: WAEL N JARJOUR
• 金额: $ 28.42万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10708321
• 关键词: Acute; Adoptive Transfer; Age; Age-Months; Animal Model; Antibodies; Antigen Presentation; Autoantibodies; Autoimmune Diseases; Autoimmune Responses; B-Lymphocytes; Cell membrane; Cell physiology; Cells; DYSF gene; Data; Defect; Dermatomyositis; Development; Disease; Distal; Enzyme-Linked Immunosorbent Assay; Exhibits; Exposure to; Extracellular Space; FOXP3 gene; Family; Genetic; Goals; Histologic; Histology; Idiopathic Inflammatory Myopathies; Immunize; Immunodeficient Mouse; Immunosuppression; Immunosuppressive Agents; Impairment; In Vitro; Inflammation; Inflammatory; Infusion procedures; Injury; Innate Immune Response; Journals; Lead; Link; Measures; Medical; Membrane; Methotrexate; Modeling; Morbidity - disease rate; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle Proteins; Muscle Weakness; Muscle function; Myoblasts; Myopathy; Myositis; Pathogenesis; Pathogenicity; Pathology; Patient-Focused Outcomes; Patients; Physiological; Play; Poloxamer 188; Poloxamers; Process; Production; Proteins; Publishing; Rag1 Mouse; Recombinants; Regulatory T-Lymphocyte; Research; Role; Sampling; Serum; Site; Skeletal Muscle; Stabilizing Agents; System; T-Lymphocyte; TRIM Motif; Testing; Therapeutic; Therapeutic Effect; Vesicle; Work; cell injury; clinical investigation; cohort; effective therapy; efficacy testing; extracellular; healing; improved outcome; in vivo; insight; link protein; lymph nodes; member; mortality; mouse model; muscular structure; mycophenolate mofetil; new therapeutic target; novel; novel therapeutic intervention; repaired; response; synaptotagmin VII; therapeutic development; therapeutic evaluation; trafficking

Project Summary Idiopathic inflammatory myopathies (IIM) are a group of inflammatory disorders characterized by muscle weakness and are associated with significant morbidity and mortality. Inflammation and muscle injury are the central features observed in histology. Both adaptive and innate immune responses are involved in the pathogenesis of IIM but the pathogenic mechanisms are not yet well defined. Current treatment options for myositis are limited and focus on the use of broad-spectrum immunosuppressive drugs that often lead to significant complications. Previous studies with synaptotagmin VII null (SytVII-/-) mice displayed impaired sarcolemmal membrane repair capacity and developed mild myositis at two months in age, suggesting that antigen presentation of internal skeletal muscle proteins may play a role in initiating or exacerbating myositis. We generated a more robust model of inflammatory myositis by combining the SytVII-/- model with scurfy mice that have a regulatory T cell deficiency (FoxP3-/Y/SytVII-/-). Adoptive transfer of lymph node cells from FoxP3- /Y/SytVII-/- mice into Rag-1-/- mice lacking both T- and B-cells results in significant muscle inflammation. This finding also links the progression of myositis with defects in sarcolemmal membrane repair. The sarcolemmal membrane repair response is a conserved response necessary to restore membrane integrity in myocytes as part of normal cellular physiology. Defects in membrane repair are linked to a variety of muscle diseases. Our previous work helped identify intracellular proteins as critical components of the membrane repair process. This application builds on our recently published work and new preliminary studies that identified novel autoantibodies in myositis patients against proteins that are essential for the membrane repair. We also established that these antibodies can alter the membrane repair capacity of skeletal muscle. We hypothesize that compromised membrane repair leads to exposure of these membrane repair proteins to the extracellular space and that the autoantibodies produced against these proteins further compromise membrane repair and exacerbate inflammation during myositis. We will test this hypothesis with three specific aims. Aim 1 will define the mechanistic role of TRIM antibodies on membrane fragility associated with myositis using various mouse models with compromised membrane repair. Aim 2 will determine if patients’ autoantibodies directed against skeletal muscle proteins linked to the membrane repair process are sufficient to compromise membrane repair. Aim 3 will test the efficacy of increasing membrane repair capacity of skeletal muscle as a novel therapeutic strategy to treat myositis. Our findings that compromised membrane repair contributes to the pathogenesis of myositis suggests a potential therapeutic strategy that could target multiple IIM.

项目摘要 特发性炎症性肌病(IIM)是一组以肌肉为特征的炎症性疾病 身体虚弱，与严重的发病率和死亡率有关。炎症和肌肉损伤是 组织学上观察到的主要特征。适应性免疫反应和先天免疫反应都参与了 IIM的发病机制尚不清楚。目前的治疗方案 肌炎是有限的，主要集中在使用广谱免疫抑制药物，这往往会导致 严重的并发症。先前对突触素VII缺失(SytVII-/-)小鼠的研究显示存在损害 肌膜修复能力，并在两个月龄时出现轻度肌炎，提示 骨骼肌内蛋白的抗原提呈可能在肌炎的发病或加重中起作用。 我们通过将SytVII-/-模型与Scrfy小鼠相结合，生成了一个更强大的炎症性肌炎模型 有调节性T细胞缺陷(FoxP3-/Y/SytVII-/-)。FoxP3-淋巴结细胞过继转移的实验研究 /Y/SytVII-/-小鼠移植到同时缺乏T细胞和B细胞的RAG-1-/-小鼠体内会导致显著的肌肉炎症。这 这一发现还将肌炎的进展与肌膜修复缺陷联系起来。肌膜 膜修复反应是恢复心肌细胞膜完整性所必需的一种保守反应。 正常细胞生理学的一部分。膜修复缺陷与多种肌肉疾病有关。我们的 以前的工作帮助确定细胞内蛋白质是膜修复过程的关键成分。这 应用建立在我们最近发表的工作和新的初步研究的基础上，这些研究发现了新的自身抗体 在肌炎患者中，可以对抗膜修复所必需的蛋白质。我们还证实，这些 抗体可以改变骨骼肌膜的修复能力。我们假设这一妥协 膜修复导致这些膜修复蛋白暴露在细胞外空间，并且 针对这些蛋白产生的自身抗体进一步损害膜修复并加剧 肌炎期间的炎症。我们将通过三个具体目标来检验这一假设。目标1将定义 TRIM抗体在不同小鼠模型肌炎相关膜脆性中的作用机制 用折衷的膜修复。目标2将确定患者的自身抗体是否针对骨骼 与膜修复过程相关的肌肉蛋白足以影响膜修复。目标3 将测试增加骨骼肌膜修复能力作为一种新的治疗策略的有效性 治疗肌炎。我们的研究发现膜修复受损与肌炎的发病机制有关 提示了一种潜在的治疗策略，可能针对多种IIM。