Myotubularin and the Pathogenesis of Myotubular Myopathy

描述(申请人提供)：先天性肌病是一组不同类型的肌肉疾病，通常在婴儿期表现为虚弱和低张力。先天性肌病虽然个别罕见，但总体上是导致儿童发病率和死亡率的重要原因。这一应用的中心是发展对肌肉形成、肌肉维护和肌肉疾病的理解，与先天性肌病有关。候选人的目标是在肌肉生物学和疾病方面建立一个研究和临床职业生涯。他的直接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研究与先天性肌病的发病机制相关的问题。具体地说，他将掌握发育中的斑马鱼的遗传和细胞生物学操作，重点是研究肌醇磷脂信号和骨骼肌中的膜运输。他将把这些技术应用于肌管蛋白的研究，肌管蛋白是一种基因产物，被认为对肌小体动力学至关重要，并被认为是肌管肌病发病机制的致病因素。他还将研究肌管蛋白和同源基因MTMR14之间的关系，MTMR14在另一种形式的中心核肌病中发生突变。该研究项目的目标是确定肌管蛋白在肌肉发育和动态平衡中的作用，并确定肌管蛋白功能障碍与肌肉疾病的关系。此外，候选人还将用各种非实验室经验来补充研究项目。这将包括参加遗传学和儿科肌肉疾病的科学课程，参加与肌肉生物学有关的年度科学会议，以及临床神经肌肉疾病的高级指导。总之，这种肌肉生物学实验室和学术培训的结合将为候选人在儿科肌肉疾病领域建立专业知识以及利用他的研究显著提高对先天性肌病的发病机制和治疗的理解提供坚实的基础。相关性(参见说明)：该应用程序与公共卫生具有高度相关性。特别是，这项研究的目的是促进对儿童肌肉疾病的了解。此外，培训计划旨在为候选人提供关键知识和专业知识，这些知识和专业知识将应用于未来旨在了解和治疗儿童肌肉疾病的研究。

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.