Sizing and Scaling in Functional Muscle Cells

项目概要/摘要 Baylies实验室的使命是提供基础研究结果，以支持更好的治疗方法。 一系列肌肉疾病。我们的目标是确定基因和机制，是必不可少的， 骨骼肌的形成和健康功能，以及这些机制在疾病状态下出错的地方 例如肌肉疾病（线虫和中枢性肌病）、肌肉萎缩（恶病质、衰老），以及 软组织癌（横纹肌肉瘤）。具体来说，该实验室旨在了解导致 骨骼肌：细胞命运的承诺，细胞融合，细胞器的运动和定位，如 细胞核和肌纤维的生长和成熟。这项研究是通过开发和结合 新的遗传学、细胞生物学、成像、分子和数学方法，使用果蝇和 哺乳动物的肌肉细胞我们目前的研究集中在一个基本问题上：是什么决定了肌肉 细胞大小？控制细胞大小的机制知之甚少。这对于骨骼尤其如此。 肌肉细胞，可能有数百个细胞核，是人体中最大的细胞之一。骨骼 肌肉细胞具有显著的能力，可以响应于运动而增加它们的大小（肥大）， 在不活动、衰老或疾病（萎缩）时尺寸减小。我们对果蝇的研究揭示了关键的核 每个参数（数量，DNA含量，大小，活性）都可以由肌肉细胞调整和协调 以产生特定的尺寸。我们还发现，肌肉细胞中的许多细胞核在数量上是不同的， 沿着肌肉纤维的长度沿着活动。我们在未来五年内追求的关键问题包括： 一个肌肉细胞产生这些区域性的差异，但在一个单一的细胞内的核全局协调？ 这种差异在其他细胞器中是否明显？同样，哪些特定的信号和机制， 建立和维持核的身份沿着肌肉细胞;什么是每个核的贡献，他们的 局部细胞质区域和整个肌肉细胞？每个细胞核如何建立其细胞质区， 是否存在地区差异？最后，在肥大或萎缩的情况下，细胞核和 细胞质特性和补偿/通信机制受到影响？总之，我们的工作将 确定在正常、肥大和萎缩条件下肌细胞大小的定义参数，及其 肌肉功能所需的生理范围。我们的研究将揭示细胞大小调节的一般原理， 提供洞察这些过程的不当调节如何导致疾病，并告知再生 针对肌肉的药物。

Project Summary/Abstract The mission of the Baylies lab is to deliver basic research findings that will support better therapies across a range of muscle diseases. Our goals are the identification of genes and mechanisms that are essential for the formation and healthy functioning of skeletal muscle, and where these mechanisms go awry in disease states such as muscular disorders (nemaline and centronuclear myopathies), muscle wasting (cachexia, aging), and soft tissue cancer (rhabdomyosarcoma). Specifically, the lab aims to understand key processes that lead to skeletal muscle: cell fate commitment, cell-cell fusion, movement and positioning of organelles such as the nucleus, and muscle fiber growth and maturation. That research is conducted by developing and combining novel genetic, cell biological, imaging, molecular and mathematical approaches, using Drosophila and mammalian muscle cells. Our current investigations focus on a fundamental question: what determines muscle cell size? The mechanisms that control cell size are poorly understood. This is particularly true for a skeletal muscle cell, which may have hundreds of nuclei and is among the largest cells in the human body. Skeletal muscle cells have a remarkable capacity to increase their size in response to exercise (hypertrophy), and to decrease in size upon inactivity, aging, or disease (atrophy). Our work in Drosophila has revealed critical nuclear parameters (number, DNA content, size, activity) that can each be adjusted and coordinated by the muscle cell to generate a particular size. We have also found that the many nuclei in a muscle cell vary in number and activity along the length of a muscle fiber. Key questions we are pursuing over the next five years include: How does a muscle cell generates these regional differences yet globally coordinate the nuclei within a single cell? Are such differences apparent in other organelles? Similarly, what are the specific signals and mechanisms that establish and maintain nuclear identity along the muscle cell; what are the contributions of each nucleus to their local cytoplasmic domain and to the entire muscle cell? How does each nucleus set up its cytoplasmic area and are there regional differences? Finally, under conditions of hypertrophy or atrophy, how are nuclear and cytoplasmic identities and the compensation/communication mechanisms impacted? Altogether, our work will identify defining parameters of muscle cell size under normal, hypertrophic and atrophic conditions, and their physiological range required for muscle function. Our studies will reveal general principles of cell size regulation, provide insight to how improper regulation of these processes results in disease, and inform regenerative medicine aimed at muscle.