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 弱点，与大量发病率和死亡率有关。炎症和肌肉损伤是 在组织学中观察到的中心特征。适应性和先天免疫反应都参与 IIM的发病机理，但病原机制尚未定义。当前的治疗选择 肌炎有限，专注于使用广谱免疫抑制药物，通常会导致 明显的并发症。先前对突触agmin vii null（Sytvii - / - ）小鼠的研究表现为受损 肌膜膜修复能力，并在两个月的年龄出现轻度肌炎，表明 内部骨骼肌蛋白的抗原表现可能在引发或加剧肌炎中发挥作用。 我们通过将SYTVII - / - 模型与Scurfy小鼠组合在一起，产生了更强大的炎症性肌炎模型 具有调节性T细胞缺乏症（FOXP3-/Y/SYTVII - / - ）。从FOXP3-的淋巴结细胞的过继转移 /y/sytvii - / - 小鼠进入rag-1 - / - 缺乏T-和B细胞的小鼠会导致肌肉感染显着。这 发现还将肌炎的进展与肌膜膜修复中的缺陷联系起来。肌符号 膜修复反应是恢复肌细胞中膜完整性所必需的保守响应 正常细胞生理的一部分。膜修复中的缺陷与多种肌肉疾病有关。我们的 先前的工作有助于将细胞内蛋白识别为膜修复过程的关键组成部分。这 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，该研究确定了新型自身抗体 在肌炎患者中针对蛋白质的蛋白质，这对于膜修复至关重要。我们还确定这些 抗体可以改变骨骼肌的膜修复能力。我们假设这被妥协 膜修复会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了膜修复并加剧 肌炎期间的炎症。我们将以三个特定的目标检验这一假设。 AIM 1将定义 修剪抗体在使用各种小鼠模型的与肌炎相关的膜脆弱性上的机械作用 膜修复受损。 AIM 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型热策略的效率 治疗肌炎。我们损害膜修复的发现有助于肌炎的发病机理 提出一种潜在的理论策略，可以针对多个IIM。