Sizing and Scaling in Functional Muscle Cells

项目总结/摘要 细胞大小是细胞的最基本和定义性特征之一。然而，控制规模的机制 我们对此知之甚少。对于肌肉细胞来说尤其如此，肌肉细胞具有显著的增加 他们的大小响应于运动，并在不活动，衰老或疾病的大小减少。长期 这项提案的目标是定义基因，机制和网络负责肌肉大小缩放下， 正常、肥大和萎缩状态。这些机制将转化为更好地理解 建立功能性肌肉和更好的肌肉治疗策略所需的基本方面 由于衰老和疾病而萎缩。这项建议的目的是确定肌肉细胞的显著特征， 通过遗传学、细胞生物学、数学建模和成像方法来确定肌肉大小。我们 将在果蝇幼虫肌肉组织中进行这些研究，利用其细胞简单，容易 细胞功能、光学清晰度的读数，以及用于成像和组织特异性 操纵体内的遗传、环境和机械因素。在目标1中，我们将收购和 对细胞和细胞器大小，特别是核分布，大小/倍性， 和活动，以确定在正常、肥大和萎缩条件下随肌肉大小缩放的那些。 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 参数来生成功能性肌肉尺寸。我们将通过基因操作来测试我们的预测。 具体测量参数。我们已经发现了新的补偿机制， 实现一个功能性的肌肉细胞：核面积可以调整，以解释核数量的差异 同样大小的肌肉。在目标2中，神经支配的局部效应，以及机械力对 将研究单个细胞核的大小和活性以及整个细胞的大小。负责改变的机制 核的大小和活动将被揭露。最后，目标3将集中于Mycobile Domain的调查 正常、肥大和萎缩肌肉的大小。我们还将数学建模和测试机制 通过其在正常、肥大和萎缩条件下产生并维持Mycobacterium结构域。 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、肥大和萎缩状态下的大小，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理， 这些过程的调节导致疾病，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.