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

这个辅导性职业发展奖的目标是促进PI向独立的 内科医生-科学家，具有神经肌肉医学的临床专业知识，并侧重于分子方面的研究 肌病的机制。应聘者是医学博士神经肌肉神经学家，有遗传学背景， 遗传性肌病的肌学、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，获得高级肌肉退行性研究的经验 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。该奖项还将有助于他过渡到拥有独立调查员的独立调查员 实验室。这也将有助于候选人实现他的长期目标，即成为一名成功和 多产的内科科学家和建立肌肉营养不良中心，专注于加快步伐 科学发现及其在肌肉退行性疾病患者护理中的应用。 进行拟议研究的环境非常好。候选人的初选 导师克里斯·韦尔博士和艾伦·佩斯特龙克博士是享誉国际的科学家和神经肌肉专家。 在培训初级教员方面有卓越记录的神经科医生。这两个不同的组合 科学家营造了一种环境，使候选人能够成为一名独立的调查员。这个 拟议的研究将描绘DNAJB6疾病突变的致病机制并开发治疗方法 肢体带状肌营养不良1D型(LGMD1D)患者的治疗策略。肌肉营养不良是一种 不同类型的无法治疗的肌肉疾病。蛋白质伴侣或热休克蛋白(HSPs)是 对骨骼肌健康至关重要。最近，发现Hsp40辅助伴侣DNAJB6的突变会导致 导致肢带型肌营养不良症1D(LGMD1D)，一种成人起病的进行性肌病，伴有空泡性和 综合肌肉病理学。DNAJB6的S在正常肌肉中的作用，以及突变如何导致肌病，尚不清楚。 需要检验的中心假设是：DNAJB6中的LGMD1D突变改变了其基线定位和 骨骼肌内的动力学(1)，抑制下游的生肌信号通路(2)，并损害其 肌原纤维应激反应(3)。 阐明DNAJB6的S作为连接肌瘤蛋白动态平衡和基因表达中枢的作用 为LGMD1D的发病机制和治疗策略以及其他原发疾病提供见解 伴病症和骨骼肌伴功能障碍的常见疾病。这份职业发展 奖励是一种理想的机制，为候选人提供有价值的研究培训，以补充他的 专注于神经肌肉疾病的临床研究，并帮助培养转化基础科学发现的技能 为肌病患者提供有效的治疗方法。

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.