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

描述(申请人提供)：包涵体肌炎(IBM)是主要的年龄相关性骨骼肌疾病，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，模拟了类似IBM的运动缺陷和病理，包括骨骼肌中AFT的积累和tau的磷酸化。这项建议调查了在转基因小鼠中调节IBM样病理严重程度的遗传和药理学因素。我们的初步数据表明，AFT的积聚在其发病机制中起着关键作用。因此，增加AFT的因素，如炎症，会加剧表型，而我们建议减少AFI的干预措施可能是延缓或治愈IBM的有效治疗策略。前两个目标是当前研究的继续。目的1确定骨骼肌炎性反应对AFT和tau的病理影响，并评估是否有抗炎药调节这些IBM样的病理改变。在Aim 2中，1将利用我们的转基因IBM模型来确定AFT免疫疗法是否改善了运动障碍和肌肉病理。我们将调查主动免疫作为IBM的潜在治疗方法的效果；这项研究的结果可能证明启动一项针对IBM患者的人类临床试验是合理的。最后一个目标(目标3)集中在肌病和痴呆症之间的分子联系，基于目前发现的这些疾病之间的遗传联系。我将产生一种新的转基因小鼠，该小鼠携带Valosin-Holding Protein(VCP)基因的临床突变，该基因与IBM/Paget病/额颞部痴呆有关。VCP上的突变可能与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有关。因此，小鼠模型将对治疗评估和研究这些不同疾病的发病机制的任何共同的分子机制都很有用。后一点值得强调，因为IBM受损的肌肉纤维中积累了许多与痴呆症相关的蛋白质，这表明可能存在对这些蛋白质的协调细胞反应；因此，从这些模型中学到的信息可能适用于阿尔茨海默病等痴呆症。此外，提供多个系列的疾病模型可能会加速该领域的研究进展。通过这一应用，我们希望增进对IBM以及痴呆症的了解，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.