The Role of Mitochondria in Inclusion Body Myositis

线粒体在包涵体肌炎中的作用

• 批准号: 10674834
• 负责人: Elie Naddaf
• 金额: $ 16.28万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674834
• 关键词: 3-Dimensional; ATP Synthesis Pathway; Age; Aging; Alzheimer' s Disease; Antigens; Autophagocytosis; Bioenergetics; Biogenesis; Biology; Biopsy; CD8B1 gene; Cell Survival; Cell physiology; Clinical Pathways; Clinical Trials; Coupling; Data; Development Plans; Disease; Doctor of Philosophy; Electron Microscopy; Etiology; Face; Failure; Female; Fiber; Future; Genes; Goals; HLA Antigens; Immune; Immunotherapy; Impairment; Inclusion Body Myositis; Infiltration; Inflammatory; Inflammatory Infiltrate; Institution; Laboratories; Link; Lipids; Literature; Medicine; Mentors; Metabolic Pathway; Mitochondria; Mitochondrial DNA; Molecular; Morphology; Muscle; Myopathy; Myositis; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurologist; Organelles; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Play; Process; Production; Protein Biosynthesis; Reactive Oxygen Species; Refractory; Research; Research Personnel; Respiration; Role; Sampling; Sarcoplasmic Reticulum; Scanning Electron Microscopy; Series; Sex Differences; Shapes; Systems Biology; T-Lymphocyte; Techniques; Testing; Therapeutic; Training; Translational Research; Vacuole; Wheelchairs; career development; cytochrome c oxidase; diagnostic biomarker; diagnostic tool; evidence base; innovation; insight; liquid chromatography mass spectrometry; mRNA sequencing; male; metabolomics; mitochondrial dysfunction; multidisciplinary; neuromuscular; new therapeutic target; novel; novel diagnostics; protein aggregation; skills; stable isotope; therapeutic target; transcriptomics

PROJECT SUMMARY/ABSTRACT Despite being the most common myopathy after the age of 50, inclusion body myositis (IBM) pathogenesis remains poorly understood. Traditionally, IBM is considered an inflammatory myopathy. However, unlike other inflammatory myopathies, IBM almost never happens before the age of 40, has histopathological features of rimmed vacuoles and protein aggregates reminiscent of other neurodegenerative diseases, and remains refractory to all forms of immunotherapy. Patients continue to progress relentlessly and most become wheelchair dependent within 20 years from onset. Therefore, there is a critical need to determine the underlying disease mechanisms that would offer a unifying holistic explanation of the involved downstream immune and degenerative processes, and help identify new therapeutic targets. Our central hypothesis is that declining mitochondrial function plays a primary role in IBM pathogenesis, which after reaching a critical threshold at a certain age, triggers downstream inflammatory and degenerative pathways. The overall objective of this application is to define the underexplored role of mitochondria in IBM pathogenesis, aiming in the long term to identify better diagnostic biomarkers and novel evidence-based therapeutic targets for clinical trials. Therefore, we aim to: 1) Characterize the mitochondria’s morphology, dynamics and interaction with other organelles in IBM, by using 3D Scanning Electron Microscopy. 2) Identify the specific molecular level of mitochondrial dysfunction in IBM by a series of cutting-edge techniques. 3) Define the disease-specific metabolomic and transcriptomic profiles of IBM. Our proposed approach will define the nature and the extent of mitochondrial dysfunction in IBM, and provide valuable insights into IBM pathogenesis focused on, but not limited to the mitochondrial pathways. The candidate is a neurologist with advanced training in Neuromuscular Medicine, Muscle Pathology and Electrodiagnostic Medicine. The goal for this application is to help him develop laboratory-based skills necessary for translational research, expertise in Electron Microscopy, and training in Systems Biology approaches. He will be guided by a multidisciplinary team of well-established researchers who have made significant contributions to the fields of mitochondrial biology, Neuromuscular medicine and Aging. These include: Jania Trushina PhD (primary mentor), Anthony J. Windebank MD, and Ian R. Lanza PhD. The career development plan combines the strengths of the candidate, the mentors and the research institution and will help enable the candidate to become a successful independent investigator.

项目总结/摘要 尽管包涵体肌炎（IBM）是50岁以后最常见的肌病， 仍然知之甚少。传统上，IBM被认为是一种炎症性肌病。然而，与其他 炎症性肌病，IBM几乎从来没有发生在40岁之前，具有组织病理学特征， 边缘空泡和蛋白质聚集体使人联想到其他神经退行性疾病， 对所有形式的免疫疗法都是难治的。患者继续无情地进步， 从发病起20年内依赖轮椅。因此，迫切需要确定 潜在的疾病机制，这将提供一个统一的整体解释，涉及下游 免疫和退化过程，并帮助确定新的治疗目标。我们的核心假设是， 线粒体功能下降在IBM发病机制中起主要作用，在达到临界水平后， 在一定年龄的阈值，触发下游炎症和退行性通路。整体 本申请的目的是确定线粒体在IBM发病机制中未充分研究的作用， 从长远来看，要确定更好的诊断生物标志物和新的循证治疗靶点， 审判因此，我们的目标是：1）表征线粒体的形态，动力学和相互作用， 其他细胞器在IBM，通过使用3D扫描电子显微镜。2)确定特定的分子水平 线粒体功能障碍在IBM的一系列尖端技术。3)定义疾病特异性 IBM的代谢组学和转录组学特征。我们提出的方法将界定的性质和程度， 线粒体功能障碍的IBM，并提供了有价值的见解IBM发病机制的重点，但不 仅限于线粒体途径。 候选人是一名神经学家，在神经肌肉医学，肌肉病理学和 电诊断医学这个应用程序的目标是帮助他发展基于实验室的技能 转化研究，电子显微镜专业知识和系统生物学培训所必需的 接近。他将由一个多学科的研究小组指导，该小组由一群已经取得了成功的研究人员组成。 对线粒体生物学、神经肌肉医学和衰老领域的重大贡献。这些 包括：Jania Trushina博士（主要导师）、Anthony J. Windebank博士和Ian R. Lanza博士职业 发展计划结合了候选人，导师和研究机构的优势， 帮助候选人成为一名成功的独立调查员。