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

项目总结 散发性包涵体肌炎(IBM)是成年人最常见的肌肉疾病 50岁，但疾病的原因尚不清楚，也没有治疗方法。为了更好地 了解这种疾病的发病机制并确定治疗靶点，我们有 开发了两种新的小鼠模型。首先，通过将人类IBM活体组织植入 在免疫功能低下的小鼠身上，我们开发了一种人类异种移植模型 该病的主要特征包括萎缩、肌内炎症、蛋白质聚集物、 和TDP-43病理改变。第二，通过在小鼠骨骼肌中特异地删除TDP-43，我们 复制了IBM的主要特征，包括萎缩、有边框的空泡和蛋白质聚集体。这个 这项建议的目的是利用这两只小鼠更好地理解IBM的发病机制 模型和验证治疗靶点。 我们相信我们已经创造了第一个临床相关的散发性IBM小鼠模型。是这样的 模型有可能对IBM的研究有用，包括机理研究和目标 验证。这个项目将独立而严格地测试两种炎症的作用 反应和受损的TDP-43剪接抑制在IBM发病机制中的作用。

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.