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

Abeta、tau 和炎症在包涵体肌炎中的致病作用

• 批准号: 7319368
• 负责人: Masashi Kitazawa
• 金额: $ 8.18万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-17 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7319368
• 关键词: Active Immunization; Active Immunotherapy; Acute; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Anti-Inflammatory Agents; Anti-inflammatory; Autoimmune Responses; Behavior; Brain; Cell Nucleus; Cell surface; Cells; Chronic; Class; Clinical; Clinical Data; Clinical Research; Clinical Trials; Code; Data; Degenerative Disorder; Dementia; Development; Disease; Disease model; Etiology; Evaluation; Exhibits; Frontotemporal Dementia; Functional disorder; Genes; Genetic; Histocompatibility Antigens Class I; Human; Immune response; Immunization; Immunotherapy; Impaired cognition; Impairment; In Vitro; Inclusion Bodies; Inclusion Body Myositis; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Intervention; Investigation; Knowledge; Learning; Link; MM form creatine kinase; Major Histocompatibility Complex; Mediating; Mentors; Modeling; Molecular; Motor; Mus; Muscle; Muscle Fibers; Muscle Weakness; Mutation; Myopathy; Myositis; Nerve Degeneration; Neurodegenerative Disorders; Osteitis Deformans; Outcome Study; Paget' s Disease; Passive Immunization; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Phenotype; Play; Process; Prosencephalon; Protein Overexpression; Proteins; Research; Research Personnel; Role; Severities; Skeletal Muscle; Skeletal system; Sporadic Inclusion Body Myopathy; Supervision; System; T-Lymphocyte; Therapeutic; Transgenic Mice; Transgenic Model; Transgenic Organisms; Ubiquitin; Up-Regulation; Vacuole; age related; base; immunoreactivity; improved; insight; motor deficit; mouse model; multicatalytic endopeptidase complex; mutant; mutant mouse model; neuron loss; novel; presenilin; programs; promoter; protein aggregate; response; tau Proteins; tau aggregation; tau phosphorylation; tool; valosin-containing protein

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.

描述（由申请人提供）：包涵体肌炎（IBM）是主要的年龄相关性骨骼肌疾病，但其病因仍然未知，也不存在有效的治疗方法。我们开发了新型转基因模型，模拟IBM样运动缺陷和病理，包括骨骼肌中的Aft积累和tau磷酸化。本提案调查的遗传和药理学因素，调节严重程度的IBM样病理转基因小鼠。我们的初步数据表明，Aft的积累在其发病机制中起着关键作用。因此，增加AFT的因素，如炎症，加剧了表型，而我们提出，减少AFI的干预措施可能是一种有效的治疗策略，以延迟或治愈IBM。前两个目标是继续目前的研究。目的1确定骨骼肌炎症反应对Aft和tau蛋白的病理影响，并评估任何抗炎剂调节这些IBM样病理。在目标2中，1将利用我们的转基因IBM模型来确定Aft免疫疗法是否改善运动缺陷和肌肉病理学。我们将研究主动免疫作为IBM潜在治疗的效果;本研究的结果可能证明IBM患者的人体临床试验的启动是合理的。最后一个目标（目标3）的重点是肌病和痴呆症之间的分子联系，基于这些疾病之间的遗传联系的当前发现。我将培育出一种新型转基因小鼠，这种小鼠的含缬氨肽蛋白（VCP）基因存在临床突变，导致IBM/佩吉特病/额颞叶痴呆。VCP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，小鼠模型将可用于治疗评价和研究这些不同疾病发病机制的任何共有分子机制。后一点值得强调，因为许多痴呆相关蛋白质积累在IBM受损的肌纤维中，这表明可能存在对这些蛋白质的协调细胞反应;因此，从这些模型中了解到的信息可能适用于阿尔茨海默病等痴呆症。此外，提供多系疾病模型可能会加速该领域的研究进展。通过这个应用程序，我们希望推进对IBM以及痴呆症的理解，并评估IBM的潜在治疗策略。