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.

项目概要 特发性炎症性肌病 (IIM) 是一组以肌肉萎缩为特征的炎症性疾病 虚弱并与显着的发病率和死亡率相关。炎症和肌肉损伤是 组织学中观察到的中心特征。适应性免疫反应和先天免疫反应都参与 IIM 的发病机制，但其发病机制尚未明确。目前的治疗方案 肌炎的治疗效果有限，重点使用广谱免疫抑制药物，这些药物往往会导致 严重的并发症。先前对突触结合蛋白 VII 无效 (SytVII-/-) 小鼠的研究显示受损 肌膜修复能力和两个月大时出现轻度肌炎，表明 内部骨骼肌蛋白的抗原呈递可能在引发或加剧肌炎中发挥作用。 我们通过将 SytVII-/- 模型与皮屑小鼠相结合，生成了更稳健的炎性肌炎模型 具有调节性 T 细胞缺陷 (FoxP3-/Y/SytVII-/-)。 FoxP3-淋巴结细胞的过继转移 将 /Y/SytVII-/- 小鼠注入缺乏 T 细胞和 B 细胞的 Rag-1-/- 小鼠中会导致明显的肌肉炎症。这 研究结果还将肌炎的进展与肌膜修复缺陷联系起来。肌膜 膜修复反应是恢复肌细胞膜完整性所必需的保守反应，如下所示 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 之前的工作有助于确定细胞内蛋白质是膜修复过程的关键组成部分。这 该应用程序建立在我们最近发表的工作和新的初步研究的基础上，这些研究确定了新型自身抗体 肌炎患者对抗膜修复所必需的蛋白质。我们还确定这些 抗体可以改变骨骼肌的膜修复能力。我们假设妥协了 膜修复导致这些膜修复蛋白暴露于细胞外空间，并且 针对这些蛋白质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 使用各种小鼠模型研究 TRIM 抗体对与肌炎相关的膜脆性的机制作用 膜修复受损。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损害膜修复。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功效 来治疗肌炎。我们的发现表明膜修复受损导致肌炎的发病机制 提出了一种可以针对多种 IIM 的潜在治疗策略。