Pathogenesis and treatment of sporadic Inclusion Body Myositis in mouse models.

小鼠模型散发性包涵体肌炎的发病机制和治疗。

• 批准号: 10199942
• 负责人: Thomas E. Lloyd
• 金额: $ 44.83万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-22 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10199942
• 关键词: Adult; Age; Aging; Animal Model; Atrophic; Attenuated; Autoimmune Diseases; Binding; Biopsy; CD8-Positive T-Lymphocytes; Cell Count; Cells; Characteristics; Clinical; Data; Degenerative Disorder; Disease; Disease model; Exons; Goals; Haplotypes; Human; Immune response; Immune system; Immunocompromised Host; Immunodeficient Mouse; Immunohistochemistry; Immunosuppression; Immunotherapy; Implant; Inclusion Body Myositis; Inflammation; Inflammatory; Inflammatory Response; Invaded; Longevity; Messenger RNA; Modeling; Mus; Muscle; Muscular Atrophy; Myopathy; Myositis; Natural regeneration; Neurodegenerative Disorders; Neurons; Nuclear; Pathogenesis; Pathologic; Pathology; Patients; RNA; RNA Splicing; RNA-Binding Proteins; Repression; Role; Secondary to; Skeletal Muscle; Sporadic Inclusion Body Myopathy; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Transplantation; Treatment Efficacy; Up-Regulation; Vacuole; Validation; Viral; Xenograft Model; Xenograft procedure; autoreactivity; base; cell type; clinically relevant; cytokine; human disease; humanized mouse; illness length; improved; in vivo Model; insight; mouse model; muscle degeneration; muscle regeneration; new therapeutic target; novel; protein TDP-43; protein aggregation; response; satellite cell; therapeutic development; therapeutic target; transcriptome; transcriptome sequencing; validation studies

PROJECT SUMMARY Sporadic Inclusion Body Myositis (IBM) is the most common muscle disease in adults over age 50, yet the cause of the disease is unknown, and there are no treatments. To better understand the pathogenesis of this disease and to identify therapeutic targets, we have developed two novel mouse models. First, by implanting human IBM biopsy tissue into immunocompromised mice, we have developed a human xenograft model that recapitulates key features of the disease including atrophy, endomysial inflammation, protein aggregates, and TDP-43 pathology. Second, by deleting TDP-43 specifically in skeletal muscle of mice, we replicated key IBM features including atrophy, rimmed vacuoles and protein aggregates. The goal of this proposal is to better understand the pathogenesis of IBM using these two mouse models and to validate therapeutic targets. We believe we have created the first clinically relevant mouse models of sporadic IBM. Such models have the potential to be useful for IBM studies including mechanistic studies and target validation. This project will independently and rigorously test both the role of the inflammatory response and the role of compromised TDP-43 splicing repression in IBM pathogenesis.

项目概要 散发性包涵体肌炎 (IBM) 是超龄成年人中最常见的肌肉疾病 50岁，但该病的病因尚不清楚，也没有治疗方法。为了更好 为了了解这种疾病的发病机制并确定治疗靶点，我们 开发了两种新颖的小鼠模型。首先，将人体 IBM 活检组织植入 针对免疫功能低下的小鼠，我们开发了一种人类异种移植模型，该模型概括了 该疾病的主要特征包括萎缩、肌内膜炎症、蛋白质聚集、 和TDP-43病理学。其次，通过特异性删除小鼠骨骼肌中的 TDP-43，我们 复制了关键的 IBM 特征，包括萎缩、边缘液泡和蛋白质聚集体。这 该提案的目标是使用这两种小鼠更好地了解 IBM 的发病机制 模型并验证治疗目标。 我们相信我们已经创建了第一个临床相关的散发性 IBM 小鼠模型。这样的 模型有可能对 IBM 研究有用，包括机制研究和目标 验证。该项目将独立、严格地测试炎症的作用 反应以及受损的 TDP-43 剪接抑制在 IBM 发病机制中的作用。