Pathogenic Role of Abeta, tau and Inflammation in Inclusion Body Myositis

描述（由申请人提供）：包体体肌炎（IBM）是主要的与年龄相关的骨骼肌疾病，其病因尚不清楚，也没有有效的治疗方法。我们开发了新的转基因模型，模拟ibm样的运动缺陷和病理，包括骨骼肌中的Aft积累和tau磷酸化。本研究旨在探讨基因和药理学因素对转基因小鼠ibm样病理严重程度的影响。我们的初步数据表明，Aft的积累在其发病机制中起关键作用。因此，增加Afi的因素，如炎症，加剧了表型，而我们建议减少Afi的干预措施可能是延迟或治愈IBM的有效治疗策略。前两个目标是当前研究的延续。目的1确定骨骼肌炎症反应对Aft和tau蛋白的病理影响，并评估任何调节这些ibm样病理的抗炎剂。在目标2中，我将利用我们的转基因IBM模型来确定Aft免疫疗法是否能改善运动缺陷和肌肉病理。我们将研究主动免疫作为一种潜在的治疗方法的效果；这项研究的结果可能证明对IBM患者开展人体临床试验是合理的。最后一个目标（目标3）侧重于肌病和痴呆之间的分子联系，基于目前发现的遗传联系这些疾病。我将产生一种新的转基因小鼠，其含有valosin-containing protein （VCP）基因的临床突变，导致IBM/Paget病/额颞叶痴呆。VCP的突变可能涉及在IBM和一些神经退行性疾病中发现的疾病相关蛋白的异常积累。因此，小鼠模型将有助于治疗评估和研究这些不同疾病发病机制的任何共享分子机制。后一点值得强调，因为许多与痴呆症相关的蛋白质在IBM中受损的肌肉纤维中积累，这表明可能存在对这些蛋白质的协调细胞反应；因此，从这些模型中获得的信息可能适用于阿尔茨海默病等痴呆症。此外，提供多种疾病模型可能会加速该领域的研究进展。通过这一应用，我们希望促进对IBM以及痴呆症的理解，并评估IBM的潜在治疗策略。

DESCRIPTION (provided by applicant): Inclusion body myositis (IBM) is the leading age-related skeletal muscle disorder, yet its etiology remains unknown, nor do effective treatments exist. We developed novel transgenic models that mimic IBM-like motor deficits and pathology, including Aft accumulation and tau phosphorylation in skeletal muscle. This proposal investigates the genetic and pharmacologic factors that modulate the severity of IBM-like pathology in transgenic mice. Our preliminary data indicate that the accumulation of Aft plays a pivotal role in its pathogenesis. Consequently, factors that augment Aft, such as inflammation, exacerbate the phenotype, whereas we propose that interventions that reduce Afi may be an effective therapeutic strategy to delay or cure IBM. The first two aims are continuation of current studies. Aim 1 determines the pathologic effect of inflammatory responses in skeletal muscle on Aft and tau and also evaluate any anti-inflammatory agents modulate these IBM-like pathology. In aim 2,1 will utilize our transgenic IBM models to determine if Aft immunotherapy ameliorates the motor deficits and myopathology. We will investigate the effect of active immunization as a potential treatment for IBM; the outcome of this study may justify the initiation of a human clinical trial with IBM patients. The last aim (aim 3) focuses on the molecular link between myopathy and dementia, based on the current finding of genetic link between these diseases. I will generate novel transgenic mice harboring a clinical mutation in the valosin-containing protein (VCP) gene, responsible for IBM/Paget disease/frontotemporal dementia. Mutations on VCP may be involved in the abnormal accumulation of disease-relevant proteins found in both IBM and some neurodegenerative disorders. Thus, the mouse models will be useful both for therapeutic evaluation and for investigating any shared molecular mechanisms underlying the pathogenesis of these distinct diseases. This latter point is worth emphasizing as many dementia-related proteins accumulate in damaged muscle fibers in IBM, suggesting that there may be a coordinated cellular response to these proteins; thus, information learned from these models may be applicable to dementias like Alzheimer disease. Furthermore, providing multiple lines of disease models may accelerate the research progress in the field. Through this application, we hope to advance the understanding of IBM as well as dementias and evaluate potential therapeutic strategies for IBM.