Molecular and Cellular Therapies for Muscular Dystrophy

肌营养不良症的分子和细胞疗法

• 批准号: 6770701
• 负责人: STANLEY C FROEHNER
• 金额: $ 137.07万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6770701
• 关键词: muscular dystrophy

Duchenne muscular dystrophy, caused by mutations in the gene encoding dystrophin, is one of the most prevalent and devastating human genetic diseases. The goal of this application is to enhance and improve therapeutic strategies and to develop the basic biology for new innovative approaches. Jeff Chamberlain will build on his expertise in DMD gene therapy by developing novel vectors able to deliver mini-dystrophins and/or myogenic regulatory genes either to muscle cells or via hematopoietic and mesenchymal stem cells. A related goal will be exploring methods for the efficient conversion of somatic stem cells into skeletal muscle. Stan Froehner will study the role of alpha-dystrobrevin, a dystrophin-associated protein, in the degeneration process. Mice lacking alpha-dystrobrevin develop muscular dystrophy through a mechanism that involves alteration in cellular signaling. The key functional domains of alpha-dystrobrevin and proteins that interact with these domains will be identified. alpha-dystrobrevin, modified to target to the membrane, will be tested for its ability to alleviate the dystrophic pathology in mdx muscle. Finally, changes in gene expression induced in muscle cells per se by the absence of alpha-dystrobrevin will be analyzed. Steve Hausehka will test the in vivo tissue specificity and long-term expression of regulatory gene cassettes designed to be optimal for packaging different therapeutic cDNAs into AAV, Lentiviral, and Adenoviral vectors. These vectors will then be used to deliver micro-, mini-, and full-length dystrophin and a variety of compensatory proteins to the dystrophic muscles of mdx4cv mice. The Administrative Core will provide general support and organize the biannual Seattle Muscular Dystrophy Conference. The Mouse Biology Core will provide assistance with functional and pathological analyses of mouse models to each project. The results derived from this integrated program project will lead to new therapeutic approaches for DMD and other diseases of muscle degeneration.

由编码肌营养不良蛋白的基因突变引起的Duchenne肌肉营养不良是最普遍，最毁灭性的人类遗传疾病之一。该应用的目的是增强和改善治疗策略，并为新的创新方法开发基本生物学。杰夫·张伯伦（Jeff Chamberlain）将通过开发能够为肌肉细胞或通过造血和间质干细胞提供小型肌营养蛋白和/或肌源性调节基因的新型载体和/或肌源性调节基因来建立他在DMD基因治疗方面的专业知识。一个相关的目标将是探索将体细胞有效转化为骨骼肌的方法。 Stan Froehner Will 研究了肌营养不良蛋白相关的蛋白在变性过程中的α-脱节蛋白的作用。缺乏α-Dystrobrevin的小鼠通过涉及细胞信号传导改变的机制发展肌营养不良。将确定与这些域相互作用的α-脱节型和蛋白质的关键功能域。 α-Dystrobrevin被修饰为靶向膜，将通过减轻MDX肌肉中营养不良病理学的能力进行测试。最后，将分析通过不存在α-脱氧蛋白的肌肉细胞中诱导的基因表达的变化。 Steve Hausehka将测试调节基因盒的体内组织特异性和长期表达，旨在将不同的治疗性CDNA包装到AAV，慢病毒和腺病毒载体中。然后，这些载体将用于将MDX4CV小鼠的营养不良肌肉传递给微型，迷你和全长肌营养不良蛋白以及各种补偿性蛋白质。 行政核心将提供一般支持，并组织一年一度的西雅图肌肉营养不良会议。小鼠生物学核心将为每个项目的小鼠模型的功能和病理分析提供帮助。该集成程序项目得出的结果将导致DMD和其他肌肉变性疾病的新治疗方法。