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

研究抗肌营养不良蛋白依赖性微管和细胞核组织及其对肌肉功能的影响

• 批准号: 10021135
• 负责人: Eric S Folker
• 金额: $ 34.25万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-25 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10021135
• 关键词: Animal Model; Biological; Biological Assay; Biological Models; Cell Nucleus; Cell physiology; Cells; Cellular Structures; Cellular biology; Collaborations; Complex; Cytoskeleton; Data; Dependence; Development; Disease; Drosophila genus; Drosophila melanogaster; Duchenne muscular dystrophy; Dystrophin; Economics; Epigenetic Process; Future; Gene Proteins; Genes; Genetic; Goals; Histologic; Impairment; Individual; Knowledge; Link; Magnetic Resonance Imaging; Measures; Mechanics; Mediating; Microtubules; Modeling; Modification; Movement; Mus; Muscle; Muscle Cells; Muscle Development; Muscle function; Muscular Dystrophies; Myopathy; Nuclear; Nuclear Envelope; Output; Pathology; Patients; Phenotype; Physiological; Physiology; Positioning Attribute; Process; Quality of life; Regulation; Research; Research Personnel; Research Proposals; Resources; Role; Sarcolemma; Skeletal Muscle; Societies; Stretching; System; Techniques; Technology; Testing; Therapeutic; Treatment Efficacy; base; cell growth regulation; design; experimental study; gene replacement therapy; mdx mouse; mechanotransduction; mouse model; muscle aging; programs; response; skeletal muscle wasting; standard measure; trafficking; virtual

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.

抽象的 由于对控制肌肉的基本细胞生物学知识有限，肌肉疾病的治疗受到阻碍 发育和肌肉功能。即使是杜氏肌营养不良症也是如此，尽管基因位点不同 该基因位点的蛋白质产物抗肌营养不良蛋白 (dystropin) 已于 20 多年前被鉴定出来。过去 20 年间 多年来，肌营养不良蛋白的许多功能已被确定，但每种功能的具体贡献 关于肌肉发育和肌肉功能的问题尚未确定。为了缩小这一差距， 本研究提案的 coPI 已建立合作关系。此次合作的目标是设计 并在不同的系统中进行实验，以全面评估各种肌肉的发育和功能 包括肌营养不良症和肌肉老化的背景。在拟议的研究中，我们将结合 模式生物果蝇的遗传和细胞生物学优势与生理学 小鼠模型的相关性以确定肌营养不良蛋白依赖性核定位的机制和 肌营养不良蛋白依赖性微管组织。此外，我们将确定机械连接 这两种肌营养不良蛋白依赖性功能之间的关系。这种机械连接将相对于 调节肌营养不良蛋白过程和时间依赖性的遗传网络。最后，我们 将评估每个过程对肌肉功能的贡献。这些实验要求我们 使用 coPI 为本研究提案开发的新兴技术以及最近的技术 由其他研究人员开发，他们将为我们的技术调整提供建议。顺利完成 拟议的研究将描述两种特定的抗肌营养不良蛋白功能，并提供一个框架 可以评估肌营养不良蛋白的其他功能以及与其他肌肉疾病相关的因素。