Genes and Therapies for Centronuclear Myopathies

描述（由申请人提供）：本项目的长期目标是了解一组密切相关的先天性肌病和肌营养不良症的分子基础，并利用这些信息为这些衰弱性疾病的患者开发治疗方法。X连锁肌管性肌病（XLM ™）是由MTM 1基因突变引起的，该基因编码肌管蛋白，一种对T小管的生物发生和功能很重要的酶脂质磷酸酶，T小管是骨骼肌中负责将信号传递到收缩器官的结构。中枢性肌病（CNM），其中XLMTM是一种亚型，也包括由RYR 1、DNM 2和BIN 1基因突变引起的形式，这些基因都是已知的或被认为在三联体的兴奋收缩偶联（ECC）中发挥作用。一些CNM家族的基因突变尚未确定。本提案的具体目的是：1）进行旨在评价XLMTM小鼠模型中肌肉生长抑制素抑制治疗潜力的研究; 2）完成导致人CNM和相关肌病的各种基因的鉴定。然后将3）在现有的或新的靶向斑马鱼突变体中对显示引起一种形式的人CNM的每个基因进行建模，以及4）将表征和开发这些品系以用于高通量药物筛选，以鉴定对原发性肌病和肌营养不良患者中的ECC的这些和相关病症具有治疗潜力的先导化合物。这些研究的成功结束将导致开发准确的基因测试，以诊断受影响儿童和家庭成员的这些情况，从而能够进行可靠的计划生育，以避免更多受影响儿童的出生。此外，识别 新的药物和小分子，减缓或防止在本研究中使用的小鼠和斑马鱼模型的弱点的发展将为新疗法的临床前测试奠定基础，这些新疗法有朝一日可能用于治疗患有这些破坏性神经肌肉疾病的儿童。

DESCRIPTION (provided by applicant): The long-term goals of this project are to understand the molecular basis for a group of closely related congenital myopathies and muscular dystrophies, and to use this information to develop therapies for patients with these debilitating conditions. X-linked myotubular myopathy (XLMTM) is caused by mutations of the MTM1 gene, which encodes myotubularin, an enzyme lipid phosphatase important for biogenesis and function of T tubules, which are the structures in skeletal muscles responsible for transmitting the signal to contract to the contractile apparatus. The centronuclear myopathies (CNMs), of which XLMTM is a subtype, also include forms caused by mutations in the RYR1, DNM2, and BIN1 genes, which are all known or thought to play a role in excitation contraction coupling (ECC) at the triads. Some families with CNM have mutations in genes that have yet to be identified. The specific aims of this proposal are 1) to conduct studies designed to evaluate the potential for myostatin-inhibition therapy in a mouse model of XLMTM and 2) to complete the identification of the various genes that cause human CNMs and related myopathies. Each of the genes shown to cause a form of human CNM will then 3) be modeled in existing or new targeted zebrafish mutants, and 4) these lines will be characterized and developed for use in high throughput drug screens to identify lead compounds with therapeutic potential for these and related disorders of ECC in patients with primary myopathies and muscular dystrophies. The successful conclusion of these studies will result in development of accurate genetic tests to diagnose these conditions in affected children and family members, allowing for reliable family planning to avoid the birth of additional affected children. Furthermore, the identification of new drugs and small molecules that slow or prevent the development of weakness in the mouse and zebrafish models used in this study will set the stage for preclinical testing of new therapies that may one day be used to treat children with these devastating neuromuscular diseases.