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.