The goal of this mentored career development award is to facilitate the PI?s transition to independence as a physician-scientist with clinical expertise in neuromuscular medicine and a research emphasis in the molecular mechanisms of myopathies. The candidate is an MD neuromuscular neurologist with a background in genetics, myology, and molecular mechanisms and therapeutic strategies for hereditary myopathies. The award will help the candidate achieve his short-term goal, to gain experience in advanced muscle degeneration research methods, including in-vivo imaging, integrative physiology techniques as well as stem cell skeletal muscle culture. The award will also help facilitate his transition to an independent investigator with an independent laboratory. It will also help position the candidate to achieve his long-term goal of becoming a successful and productive physician scientist and establishing a muscular dystrophy center focused on accelerating the pace of scientific discovery and its application to the care of individuals with myodegenerative diseases. The environment in which the proposed research will be conducted is outstanding. The candidate?s primary mentors, Drs. Chris Weihl and Alan Pestronk, are internationally respected scientists and neuromuscular neurologists with proven track records of excellence in training junior faculty. The merger of these two diverse scientists fosters an environment that will allow the candidate to become an independent investigator. The proposed research will delineate the pathomechanism of DNAJB6 disease mutations and develop treatment strategies for limb girdle muscular dystrophy type 1D (LGMD1D) patients. Muscular dystrophies are a heterogeneous group of untreatable muscle diseases. Protein chaperones, or heat shock proteins (HSPs) are critical for skeletal muscle health. Recently mutations in DNAJB6, an HSP40 co-chaperone, were found to cause limb girdle muscular dystrophy 1D (LGMD1D), an adult onset progressive myopathy with vacuolar and aggregate myopathology. DNAJB6?s role in normal muscle, and how mutations cause myopathy, is unknown. The central hypotheses to be tested are: LGMD1D mutations in DNAJB6 alter its baseline localization and kinetics within skeletal muscle (1), suppress downstream myogenic signaling pathways (2), and impair their response to myofibrillar stress (3). Clarifying DNAJB6?s role as a central hub linking sarcomeric protein homeostasis with gene expression will provide insights into LGMD1D pathogenesis and therapeutic strategies as well as for other primary chaperonopathies and common disorders of skeletal muscle chaperone dysfunction. This career development award is an ideal mechanism to provide the candidate with valuable research training to complement his clinical focus in neuromuscular disorders and help develop a skill set for translating basic science discoveries into effective therapies for patients with myopathies.
Muscular dystrophies are a disabling and often fatal form of hereditary muscle disease. No proven therapies exist for many forms. This study will explore the pathogenesis of limb girdle muscular dystrophy type 1D (LGMD1D) due to mutations in the protein chaperone DNAJB6. Understanding DNAJB6?s role as a central hub linking myofibrillar protein homeostasis with gene expression as part of a skeletal muscle stress response will be important for LGMD1D and other common disorders of muscle.