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The Role of DNAJB6 in Muscle and the Impact of LGMD1D Mutations

DNAJB6 在肌肉中的作用以及 LGMD1D 突变的影响

基本信息

批准号：
10674751
负责人：
Andrew Findlay
金额：
$ 13.91万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10674751
关键词：
AKT1 gene Acceleration Adult Animal Model Area Award Basic Science Biochemical Biological Assay Biopsy Caring Cell Nucleus Cell model Clinical Complement Data Disease Environment Faculty Fluorescence Fostering Foundations Functional disorder Gene Expression Genetic Goals Health Heat shock proteins Image Immunoelectron Microscopy Immunoprecipitation Impairment Individual Infrastructure Inherited Injury International K-Series Research Career Programs Kinetics Knock-in Knock-in Mouse Knock-out Knowledge Laboratories Limb-Girdle Muscular Dystrophies Link Luciferases Medicine Mentors Methods Modeling Molecular Molecular Chaperones Movement Mus Muscle Muscle Development Muscle Fibers Muscular Dystrophies Mutation Myoblasts Myopathy Neurologist Neurology Neuromuscular Diseases Pathogenesis Pathology Patients Phosphotransferases Physicians Physiology Positioning Attribute Productivity Protein Dephosphorylation Protein Kinase Proteins Records Research Research Methodology Research Personnel Research Proposals Research Training Role Sarcomeres Scientist Signal Pathway Signal Transduction Skeletal Muscle Stress Techniques Testing Therapeutic Time Training Translating Universities Washington biological adaptation to stress effective therapy experience experimental study glycogen synthase kinase 3 beta improved in vivo in vivo imaging induced pluripotent stem cell insight interest knock-down mouse model muscle degeneration muscle hypertrophy mutant myogenesis neuromuscular pharmacologic protein folding proteostasis repaired response response to injury skeletal disorder skeletal stem cell skills success treatment strategy

项目摘要

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.

这个指导职业发展奖项的目标是促进PI向独立的过渡