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

基本信息

批准号：
7486221
负责人：
Masashi Kitazawa
金额：
$ 8.36万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-17 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7486221
关键词：
Active Immunization Active Immunotherapy Acute Affect Alzheimer&apos s Disease Alzheimer&apos 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&apos 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

项目摘要

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）是主要的与年龄相关的骨骼肌疾病，但其病因仍不清楚，也不存在有效的治疗方法。我们开发了模仿 IBM 样运动缺陷和病理学的新型转基因模型，包括骨骼肌中的 Aft 积累和 tau 磷酸化。该提案研究了调节转基因小鼠中 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 的积累在其发病机制中发挥着关键作用。因此，炎症等增强 Aft 的因素会加剧表型，而我们提出减少 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。目标 1 确定骨骼肌炎症反应对 Aft 和 tau 蛋白的病理影响，并评估调节这些 IBM 样病理学的任何抗炎药物。目标 2,1 将利用我们的转基因 IBM 模型来确定 Aft 免疫疗法是否可以改善运动缺陷和肌病理学。我们将研究主动免疫作为 IBM 潜在治疗方法的效果；这项研究的结果可能证明对 IBM 患者进行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，基于目前对这些疾病之间遗传联系的发现。我将培育出含有缬洛辛蛋白 (VCP) 基因临床突变的新型转基因小鼠，该基因导致 IBM/佩吉特病/额颞叶痴呆。 VCP 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估和研究这些不同疾病发病机制背后的任何共同分子机制。后一点值得强调，因为许多与痴呆相关的蛋白质在 IBM 受损的肌纤维中积累，这表明细胞可能对这些蛋白质有协调的反应；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，提供多种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，我们希望增进对 IBM 和痴呆症的了解，并评估 IBM 的潜在治疗策略。