Sarcoglycan in Myopathy and Muscle Membrane Stability

肌聚糖在肌病和肌膜稳定性中的作用

• 批准号: 8915736
• 负责人: Elizabeth M McNally
• 金额: $ 37.77万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915736
• 关键词: Animal Model; Antisense Oligonucleotides; Award; Binding Proteins; Cardiac; Cardiac Myocytes; Cells; Chromosomes, Human, Pair 9; Complex; Data; Defect; Disease; Disease Outcome; Duchenne muscular dystrophy; Dyes; Dystrophin; Dystrophin-Associated Proteins; Etiology; Exons; Fibroblasts; Fibrosis; Funding; Gene Expression; Gene Mutation; Gene Transfer Techniques; Genes; Genetic; Heart; Heart Function Tests; Heart Injuries; Hereditary Disease; Human; In Vitro; Individual; Injury; Knockout Mice; Limb-Girdle Muscular Dystrophies; Maps; Measures; Membrane; Modeling; Mus; Muscle; Muscle Cells; Muscle function; Muscular Dystrophies; Muscular dystrophy cardiomyopathy; Mutation; Myocardium; Myopathy; Natural regeneration; Nature; Outcome; Pathway interactions; Patients; Process; Proteins; Quantitative Trait Loci; Role; Sarcoglycans; Sarcolemma; Skeletal Muscle; Striated Muscles; Testing; Therapeutic; Transforming Growth Factor beta; Variant; Walking; Work; design; exon skipping; fly; gamma Sarcoglycan; genome-wide; heart function; improved; in vivo; muscle regeneration; muscular dystrophy mouse model; outcome forecast; prevent; public health relevance; repaired; research study; uptake

DESCRIPTION (provided by applicant): This is a renewal application to study the sarcoglycan complex in striated muscle, and specifically the role of this complex in promoting sarcolemmal stability. Mutations in the genes encoding the sarcoglycan subunits produce a fragile sarcolemma that is susceptible to disruption. Sarcolemmal disruption is a hallmark feature associated with many different etiologies of muscle and heart injury. In the case of primary sarcoglycan gene mutations, there is ongoing injury to striated muscle, both heart and skeletal muscle. In skeletal muscle, where regeneration is robust, there is insufficient regeneration to keep pace with injury, and ultimately there is replacement of myocytes and cardiomyocytes by fibrosis, leading to weakness. The process of sarcolemmal instability is seen in humans with sarcoglycan gene mutations, as it is in those with dystrophin gene mutations, since the sarcoglycans are dystrophin-associated proteins. This proposal for continued work is justified by the need to develop approaches to stabilize the sarcolemma. Such approaches, if successful, are expected to provide a potential therapeutic for individuals with sarcoglycan gene mutation. Importantly, understanding mechanisms to stabilize the sarcolemma of heart and muscle could also potential yield improved approaches towards treating or preventing other defects that compromise sarcolemmal integrity. In the prior funding period, we proposed to use an unbiased genomewide approach to map modifiers of muscular dystrophy. We successfully did this, identifying Ltbp4, the latent TGFbeta binding protein, as a modifier for murine muscular dystrophy. We extended these findings by showing that LTBP4 also modifies walking in Duchenne Muscular Dystrophy, highlighting the importance and relevance of this approach. As proposed, we used the superhealing MRL strain to identify genetic loci that modify muscle and heart function in mouse models of muscular dystrophy. We now outline experiments to study candidate modifier genes from a chromosome 9 locus that regulates the heart in muscular dystrophy. Identifying modifiers for muscular dystrophy and cardiomyopathy points to pathways that we can exploit for prognosis and ultimately for therapy since these pathways, by design, can influence the outcome of disease. Additionally, during the prior funding period, we developed significant preliminary data identifying a minimal unit of gamma-sarcoglycan that is sufficient to improve muscle and heart function. The rationale for developing and testing this minimal unit of gamma- sarcoglycan, which we termed mini-gamma, is to justify the use of exon skipping as a treatment for LGMD2C.

描述（由申请人提供）：这是一项更新申请，旨在研究横纹肌中的肌聚糖复合物，特别是该复合物在促进肌层稳定性方面的作用。编码肌聚糖亚基的基因突变会产生易受破坏的脆弱肌膜。肌上皮破坏是与许多不同病因的肌肉和心脏损伤相关的标志性特征。在原发性肌聚糖基因突变的情况下，对横纹肌，心脏和骨骼肌都有持续的损伤。在骨骼肌中，再生能力很强，但再生能力不足以跟上损伤的速度，最终导致肌细胞和心肌细胞被纤维化取代，导致虚弱。肌层不稳定的过程在肌萎缩蛋白基因突变的人群中可见，因为肌萎缩蛋白与肌萎缩蛋白相关。由于需要开发稳定肌膜的方法，因此建议继续开展工作是合理的。这种方法，如果成功的话，有望为患有肌聚糖基因突变的个体提供潜在的治疗方法。重要的是，了解稳定心脏和肌肉肌膜的机制也可能为治疗或预防损害肌膜完整性的其他缺陷提供改进的方法。在之前的资助期内，我们建议使用无偏倚的全基因组方法来绘制肌肉萎缩症的修饰因子。我们成功地做到了这一点，鉴定出Ltbp4，一种潜在的tgfβ结合蛋白，作为小鼠肌肉萎缩症的修饰剂。我们通过显示LTBP4也改变杜氏肌营养不良症患者的行走来扩展这些发现，强调了这种方法的重要性和相关性。正如所提出的，我们使用超愈合MRL菌株来鉴定肌肉萎缩症小鼠模型中改变肌肉和心脏功能的遗传位点。我们现在概述的实验，以研究候选修饰基因从第9染色体位点，调节心脏在肌肉萎缩症。确定肌萎缩症和心肌病的修饰因子指出了我们可以用于预后和最终治疗的途径，因为这些途径可以通过设计影响疾病的结果。此外，在之前的资助期间，我们开发了重要的初步数据，确定了足以改善肌肉和心脏功能的最小单位-肌聚糖。开发和测试这种最小单位的伽玛-肌聚糖，我们称之为迷你伽玛，是为了证明使用外显子跳跃作为LGMD2C治疗的合理性。