Sizing and Scaling in Functional Muscle Cells

项目摘要/摘要 单元格大小是单元格最基本和最具决定性的特征之一。然而，控制大小的机制 人们对此了解甚少。对于肌肉细胞来说尤其如此，肌肉细胞具有惊人的增加能力 他们的大小是对运动的反应，并在不活动、衰老或疾病时减少。长期的 这项提议的目标是定义在以下条件下负责肌肉大小扩大的基因、机制和网络 正常、肥大和萎缩状态。这些机制将把两者转化为更好的理解 建立有功能的肌肉所需的基本方面，以及更好的肌肉治疗策略 由于衰老和疾病导致的萎缩。这个提案的目的是定义肌肉细胞的显著特征。 使用遗传学、细胞生物学、数学建模和成像方法来确定肌肉大小。我们 将在果蝇幼虫肌肉系统中进行这些研究，利用其细胞简单、容易 细胞功能、光学清晰度的读数，以及用于成像和特定组织的高级工具的可用性 在体内对遗传、环境和机械因素的操纵。在目标1中，我们将获得和 对细胞和细胞器大小，特别是核分布，大小/倍性， 和活动度，以确定在正常、肥大和萎缩条件下随肌肉大小而扩大的那些。 我们将使用该模型来预测特定参数的重要性以及这些参数之间的相互关系 产生功能性肌肉大小的参数。我们将通过基因操作来检验我们的预测 具体的测量参数。我们已经发现了新的补偿机制，这些机制被用来 获得有功能的肌肉细胞：核面积可以调整，以适应核数量的差异 在相同大小的肌肉中。在目标2中，神经支配的局部效应，以及机械力对 将调查单个核的大小和活性以及整体细胞大小。负责改变的机制 核的大小和活动将被揭开。最后，目标3将侧重于肌核结构域的研究 正常、肥大和萎缩肌肉的大小。我们还将对机制进行数学建模和测试 通过它在正常、肥大和萎缩的条件下创建和维持肌核域。 总之，这些实验和计算方法将确定肌肉细胞的定义参数 正常、肥大和萎缩条件下的大小以及肌肉所需的生理范围 功能。这些数据将揭示细胞大小调节的一般原则，提供对如何不适当的洞察 对这些过程的调控会导致疾病，并为针对肌肉的再生医学提供信息。

Project Summary/Abstract Cell size is one of the most basic and defining features of a cell. However, the mechanisms controlling size are poorly understood. This is particularly true for muscle cells, which have a remarkable capacity to increase their size in response to exercise, and to decrease in size upon inactivity, aging, or disease. The long-term goal of this proposal is to define genes, mechanisms, and networks responsible for muscle size scaling under normal, hypertrophic, and atrophic conditions. These mechanisms will translate both to a better understanding of fundamental aspects required to build a functioning muscle and to better strategies for treating muscle atrophy due to aging and disease. The objective of this proposal is to define salient features of the muscle cell that determine muscle size using genetic, cell biological, mathematical modeling and imaging approaches. We will perform these studies in the Drosophila larval musculature, taking advantage of its cellular simplicity, easy readouts for cell function, optical clarity, and the availability of advanced tools for imaging and tissue-specific manipulation of genetic, environmental, and mechanical factors in vivo. In Aim 1, we will acquire and mathematically model measurements of cell and organelle size, particularly of nuclear distribution, size/ploidy, and activity, to determine those that scale with muscle size under normal, hypertrophic and atrophic conditions. We will use this model to predict the importance of specific parameters and interrelationships between these parameters to generate functional muscle sizes. We will test our predictions by genetically manipulating the specific measured parameters. Already we have found novel compensatory mechanisms that are invoked to achieve a functioning muscle cell: nuclear area can be adjusted to account for differences in nuclear numbers in the same sized muscle. In Aim 2, the localized effects of innervation, and the effects of mechanical forces on individual nuclei size and activity and overall cell size, will be investigated. Mechanisms responsible for altering nuclear size and activity will be uncovered. Lastly, Aim 3 will focus on the investigation of Myonuclear Domain sizes in normal, hypertrophic and atrophic muscles. We will also mathematically model and test mechanisms by which Myonuclear domains are created and maintained under normal, hypertrophic and atrophic conditions. Altogether, these experimental and computational approaches will identify defining parameters of muscle cell size under normal, hypertrophic and atrophic conditions, and their physiological range required for muscle function. These data 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.