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

• 批准号: 9806316
• 负责人: Andrew Findlay
• 金额: $ 13.91万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/9806316
• 关键词: AKT1 gene; 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; Pharmacology; Phosphorylation; Phosphotransferases; Physicians; Physiology; Positioning Attribute; Protein Kinase; Proteins; Records; Research; Research Methodology; Research Personnel; Research Proposals; Research Training; Role; Sarcomeres; Scientist; Signal Pathway; Signal Transduction; Skeletal Muscle; Stem cells; 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; protein folding; proteostasis; repaired; response; response to injury; skeletal disorder; skills; success; treatment strategy

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.

这一指导职业发展奖的目标是促进PI的过渡到独立， 具有神经肌肉医学临床专业知识的医生-科学家， 肌病的机制。候选人是一位具有遗传学背景的神经肌肉神经学家， 遗传性肌病的分子机制和治疗策略。该奖项将 帮助候选人实现他的短期目标，获得先进的肌肉退化研究经验 方法，包括体内成像，综合生理学技术以及干细胞骨骼肌 文化该奖项还将有助于促进他过渡到一个独立的调查员， 实验室这也将有助于定位候选人，以实现他的长期目标，成为一个成功的， 多产的医生科学家和建立一个肌肉萎缩症中心，专注于加快步伐 科学发现及其应用于患有肌肉退行性疾病的个体的护理。 进行拟议研究的环境是杰出的。候选人的初选 导师Chris Weihl博士和Alan Pestronk博士是国际知名的科学家， 在培训初级教员方面有着卓越记录的神经科医生。这两个不同的合并 科学家培养一个环境，使候选人成为一个独立的调查员。的 拟议的研究将描述DNAJB 6疾病突变的病理机制，并开发治疗方法。 1D型肢带型肌营养不良症（LGMD 1D）患者的治疗策略。肌营养不良是一 无法治疗的肌肉疾病的异质群体。蛋白质伴侣，或热休克蛋白（HSP）， 对骨骼肌健康至关重要。最近发现，HSP 40共伴侣DNAJB 6的突变， 引起肢带型肌营养不良1D（LGMD 1D），一种成人发病的进行性肌病， 综合性肌肉病理学。DNAJB 6在正常肌肉中的作用以及突变如何导致肌病尚不清楚。 待检验的中心假设是：DNAJB 6中的LGMD 1D突变改变了其基线定位， 骨骼肌内的动力学（1），抑制下游肌源性信号通路（2），并损害其 肌原纤维应激反应（3）。 阐明DNAJB 6作为连接肌节蛋白稳态与基因表达的中心枢纽的作用， 为LGMD 1D的发病机制和治疗策略以及其他主要的 伴侣蛋白病和骨骼肌伴侣蛋白功能障碍的常见病症。这种职业发展 奖励是一个理想的机制，为候选人提供有价值的研究培训，以补充他的 神经肌肉疾病的临床重点，并帮助发展一套技能，翻译基础科学发现 用于肌病患者的有效治疗。