The mechanisms and functions of nuclear spacing in muscle development

核间距在肌肉发育中的机制和功能

• 批准号: 10733794
• 负责人: Eric S Folker
• 金额: $ 31.3万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733794
• 关键词: Ablation; Address; Animals; Behavior; Binding; Binding Proteins; Biological; Biological Assay; Cell Nucleus; Cell physiology; Cells; Chimeric Proteins; Complex; Cytoskeleton; Data; Development; Disease; Drosophila melanogaster; Duchenne muscular dystrophy; Dystrophin; Embryo; Eukaryota; Genes; Genetic; Goals; Golgi Apparatus; Growth; Homeostasis; Imaging Device; Impairment; Individual; Intuition; Investigation; Kinesin; Knowledge; Larva; Lasers; Maintenance; Manuscripts; Measures; Membrane; Methods; Microscopy; Microtubule-Organizing Center; Microtubules; Modeling; Molecular; Movement; Mus; Muscle; Muscle Cells; Muscle Development; Muscle Fibers; Muscle function; Mutate; Myopathy; Nature; Nuclear; Outcome; Pathogenesis; Population; Positioning Attribute; Prevalence; Process; Property; Proteins; Publishing; Regulation; Research; Role; Sarcolemma; Series; Slide; Testing; Work; cellular development; density; experimental study; genetic approach; in vivo; insight; mutant

Summary Nuclear movement is evolutionarily conserved throughout eukaryotes, a testament to the fundamentally important nature of this process. The importance of this process is most evident in syncytial muscle cells, which move their nuclei to maximize the distance between each nucleus and its neighbors, a process thought to establish a series of independent myodomains. Furthermore, mispositioned nuclei in muscle cells are prevalent in muscle disease. In recent years, dozens of proteins have been implicated in the movement and spacing of nuclei, but their mechanisms of action, and the consequences of nuclear spacing, remain elusive. The goal of the proposed research is to fill this critical gap in knowledge. Specifically, we will define the features of the microtubule cytoskeleton that are critical for both moving nuclei to establish the spacing and anchor nuclei to maintain the spacing. Only recently have the molecular, physical, and imaging tools emerged to make it possible to address these mechanistic questions in vivo. In the proposed research we will generate and test mutant proteins that target the microtubule specific functions of pleitropic proteins to isolate the specific contribution of the microtubule interactions. We will then apply our recently developed analyses of nuclear movement and microtubule organization combined with classical genetic approaches to determine the genetic and molecular mechanisms by which these factors move and anchor nuclei during muscle development. Within this work we will test whether two emergent properties of the microtubule cytoskeleton, branching and sliding contribute to nuclear spacing in muscle. Finally, we will directly tie these data to disease pathogenesis by determining how dystrophin, the gene mutated in the most common and debilitating muscle disease contributes to these processes. Successful completion of these aims will provide the first mechanistic understanding of nuclear movement in an in-tact developing muscle cell making it possible to manipulate nuclear spacing to understand how the position of the nucleus impacts its function.

概括 核运动在整个真核生物中都是在进化上保守的，这证明了这一点 这个过程的重要性质。该过程的重要性在合成肌肉细胞中最明显， 哪个移动其核以最大化每个核与邻居之间的距离，这是一个思想的过程 建立一系列独立的肌关系。此外，肌肉细胞中的核位核是 在肌肉疾病中流行。近年来，数十种蛋白质与运动有关 核的间距，但是它们的作用机理以及核间距的后果仍然难以捉摸。 拟议的研究的目的是填补知识的关键空白。具体来说，我们将定义 微管细胞骨架的特征，这对于移动核建立间距和 锚固核以维持间距。直到最近才出现分子，物理和成像工具 为了使体内解决这些机械问题。在拟议的研究中，我们将产生 并测试靶向全脂蛋白的微管特定功能的突变蛋白，以分离 微管相互作用的特定贡献。然后，我们将应用我们最近开发的分析 核运动和微管组织与经典的遗传方法相结合 这些因素在肌肉期间移动和锚定核的遗传和分子机制 发展。在这项工作中，我们将测试微管细胞骨架的两个新兴特性， 分支和滑动有助于肌肉的核间距。最后，我们将把这些数据直接将 通过确定肌营养不良蛋白是如何在最常见和令人衰弱的肌肉中突变的肌营养物的发病机制 疾病有助于这些过程。这些目标的成功完成将提供第一个机械 理解在发育中发育的肌肉细胞中的核运动，使操纵有可能 核间距了解核的位置如何影响其功能。