Investigating dystrophin-dependent organization of microtubules and nuclei and their impact on muscle function

摘要 肌肉疾病的治疗因对支配肌肉的基本细胞生物学知识有限而受到阻碍。 发育和肌肉功能。即使是Duchenne肌营养不良症也是如此，尽管存在基因位点 而该基因位点的蛋白质产物，营养不良蛋白，在20多年前就被发现了。在过去的20年里 多年来，已经确定了抗肌营养不良蛋白的许多功能，但每种功能的具体贡献 对肌肉发育和肌肉功能的影响尚未确定。为了缩小这一差距， 这项研究提案的COPI已经建立了合作关系。这次合作的目标是设计 并在不同的系统中进行实验，以充分评估各种肌肉的发育和功能 包括肌肉营养不良和肌肉老化。在拟议的研究中，我们将结合 模式生物黑腹果蝇的遗传和细胞生物学强度 小鼠模型与识别dystrophin依赖的核定位和 肌营养不良蛋白依赖的微管组织。此外，我们将确定机械连接 这两种肌营养不良蛋白依赖的功能之间。这种机械连接将相对于以下因素确定 调节这一过程的遗传网络和对Dystrophin的时间依赖性。最后，我们 将评估每个过程对肌肉功能的贡献。这些实验使我们有必要 使用COPIS为这项研究提案开发的紧急技术，以及最近的那些 由其他研究人员开发，他们将建议我们适应他们的技术。成功完成 拟议的研究将描述两个特定的肌营养不良蛋白功能，并提供一个框架，通过它 可以评估抗肌营养不良蛋白的其他功能，以及与其他肌肉疾病有关的因素。

Abstract The treatment of muscle disease is hindered by limited knowledge of the basic cell biology that governs muscle development and muscle function. This is true even of Duchenne muscular dystrophy despite the gene locus and the protein product of that gene locus, dystrophin, being identified over 20 years ago. During the last 20 years, numerous functions for dystrophin have been identified, yet the specific contribution of each function makes with regards to muscle development and muscle function have not been determined. To close this gap, the coPIs of this research proposal have established a collaboration. The goal of this collaboration is to design and execute experiments in divergent systems to fully evaluate muscle development and function in a variety of contexts including muscular dystrophy and muscle aging. In the proposed research we will combine the genetic and cell biological strengths of the model organism Drosophila melanogaster with the physiological relevance of mouse models to identify the mechanisms of dystrophin-dependent nuclear positioning and dystrophin-dependent microtubule organization. Furthermore, we will determine the mechanistic connection between these two dystrophin-dependent functions. This mechanistic connection will be determined relative to both the genetic networks that regulate the process and the temporal dependence for dystrophin. Finally, we will evaluate the contribution of each process to muscle function. These experiments necessitate that that we use emergent techniques that have been developed by the coPIs for this research proposal, and those recently developed by other researchers who will advise our adaptations of their technology. Successful completion of the proposed research will delineate two specific dystrophin functions and provide a framework by which additional functions for dystrophin, and factors linked to other muscle disorders, can be evaluated.