Myotubularin and the Pathogenesis of Myotubular Myopathy

描述（由申请人提供）：先天性肌病是一组异质性肌肉疾病，通常在婴儿期表现为无力和张力不足。先天性肌病个别罕见，但总体上是儿童发病率和死亡率的重要原因。这种应用集中在对先天性肌病的肌肉形成、肌肉维持和肌肉疾病的理解的发展上。候选人的目标是在肌肉生物学和疾病方面建立研究和临床生涯。他的近期目标是熟练掌握用于研究斑马鱼骨骼肌的技术，并将这些技术应用于先天性肌病发病机制的研究。具体来说，他将掌握发育中的斑马鱼的遗传和细胞生物学操作，重点是检查骨骼肌中的磷酸肌苷信号和膜运输。他将把这些技术应用于肌小管蛋白的研究，这是一种基因产物，假设对内体动力学至关重要，并且已知是肌小管肌病发病机制的致病因素。他还将研究肌小管蛋白与同源基因MTMR14之间的关系，该基因在另一种形式的核中心性肌病中发生突变。本研究的目的是建立肌小管蛋白在肌肉发育和体内平衡中的功能，并确定肌小管蛋白功能障碍与肌肉疾病之间的关系。此外，候选人将以各种非实验室经验补充研究项目。这些包括参加遗传学和小儿肌肉疾病的科学课程，参加与肌肉生物学相关的年度科学会议，以及临床神经肌肉疾病的高级指导。总之，这种肌肉生物学的实验室和学术训练的结合将为候选人在儿科肌肉疾病领域建立专业知识的长期目标提供坚实的基础，并利用他的研究显著推进对先天性肌病发病机制和治疗的理解。相关性（见说明）：本应用程序与公共卫生高度相关。特别是，这项研究旨在提高对儿童肌肉疾病的认识。此外，该培训计划旨在为候选人提供关键的知识和专业知识，这些知识和专业知识将应用于旨在理解和治疗儿童肌肉疾病的未来研究。

DESCRIPTION (provided by applicant): Congenital myopathies are a heterogeneous group of muscle diseases that commonly present as weakness and hypotonia in infancy. Congenital myopathies are individually rare, but overall represent a significant cause of childhood morbidity and mortality. This application is centered on the development of an understanding of muscle formation, muscle maintenance and muscle disease as relates to congenital myopathies. The candidate's goal is to establish a research and clinical career in muscle biology and disease. His immediate goal is develop proficiency in the techniques utilized to study skeletal muscle in zebrafish, and to apply those techniques to the study of a question relevant to the pathogenesis of congenital myopathies. Specifically, he will master genetic and cell biologic manipulations in the developing zebrafish, with a focus on the examination of phosphoinositide signaling and membrane trafficking in skeletal muscle. He will apply these techniques to the study of myotubularin, a gene product hypothesized to be critical for endosomal dynamics and known to be the causative factor in the pathogenesis of myotubular myopathy. He will also study the relationship between myotubularin and the homologous gene MTMR14, which is mutated in another form of centronuclear myopathy. The goal of the research project is to establish the function of myotubularins in muscle development and homeostasis, and to determine the relationship between myotubularin dysfunction and muscle disease. In addition, the candidate will supplement the research project with a variety of non-laboratory experiences. These will include attendance at scientific courses in genetics and in pediatric muscle disease, participation in annual scientific meetings relevant to muscle biology, and advanced instruction in clinical neuromuscular disease. In all, this combination of laboratory and academic training in muscle biology will provide a strong foundation for the candidate's long term goal of establishing expertise in the field of pediatric muscle disease, and of utilizing his research to significantly advance understanding of the pathogenesis and treatment of congenital myopathies. RELEVANCE (See instructions): This application has high relevance to public health. In particular, the research is aimed at advancing the understanding of muscle disease in children. In addition, the training program is designed to provide the candidate with critical knowledge and expertise that will be applied to future studies aimed at understanding and treating childhood muscle disease.