Design Principles of Size-Control of Organelles Growing in a Shared Pool of their Building Blocks

摘要 活细胞包含各种可区分的部分，称为细胞器，它们具有特定的大小和 具体功能。这些细胞器生长在它们各自构建块的共享池中，并且显著地 能够在快速交换构建块的情况下保持其结构。这引发了一个问题：如何 细胞器的大小是否由细胞主动控制，这些细胞器生长在一个共享的构件池中？几年来 生化实验已经揭示了与这些结构有关的过多蛋白质，然而，由于 所涉及的变量的高维度，它们如何共同作用来创建大小合适的细胞器是 仍然不能很好地理解。因此，数学建模和模拟提供了一种令人兴奋的方法来解决 这些问题，还有一个额外的好处，就是确定关键的可调旋钮，以便生物化学家简化运行 实验。在过去的几年里，在肌动蛋白缆线和鞭毛等细胞器上使用这些技术，我 通过构建块或关键附件池的减少，确定了对大小的负面反馈 细胞器特有的蛋白质，对控制生长中的细胞器的大小至关重要。值得注意的是，关键是 我们建议的实验旋钮后来被用来测试我的定量模型的预测。 我的结果使我们了解了建造单一结构的设计原则，但如何竞争 结构组装并保持其大小，同时共享公共的构造块池保持开放 问题。在接下来的五年里，我们的目标是定量分析细胞用来分享 相互竞争的结构之间的积木。参与细胞器分解的蛋白质提供了一种解决方案- 除了拆卸预先存在的结构外，它们还可以提供关键的长度感应反馈，以 共享公共构建块池的各个结构。使用模拟方案和理论工具 作为我的先驱，我们将识别特定拆卸机制的明显特征，并定量 描述它们对不同竞争结构之间共享公共资源的影响。vbl.使用 肌动蛋白结构和核仁作为我们的模型系统，我们将设计理论驱动的实验来验证我们的 与已经建立的合作进行预测，并使用实验可调的旋钮来区分 在不同的机制之间，细胞用来在相互竞争的结构之间共享构建块。一个 定量了解影响细胞器生长的分子机制将加速细胞器的发育 对抗许多人类神经退行性疾病的新疗法，如肌萎缩侧索硬化症 (肌动蛋白组装异常)和帕金森氏症和阿尔茨海默病(核仁异常)。

ABSTRACT Living cells contain a variety of distinguishable parts called organelles which have characteristic sizes and specific functions. These organelles grow in a shared pool of their respective building blocks, and are remarkably able to maintain their structure despite a rapid exchange of their building blocks. This prompts a question: how are the sizes of organelles growing in a shared pool of building blocks actively controlled by the cell? Years of biochemical experiments have revealed a plethora of proteins involved with these structures, yet, due to the high-dimensionality of the variables involved, how they all work together to create properly-sized organelles is still not well understood. Mathematical modeling and simulations, thus, provide an exciting avenue to tackle these questions, with the added benefit of identifying key tunable knobs for biochemists to run streamlined experiments. Over the last few years, using these techniques on organelles like actin cable and flagellum, I identified that a negative feedback to the size, mediated by a diminishing pool of building blocks or key accessory proteins specific to the organelle, was critical in controlling the size of a growing organelle. Significantly, the key experimental knobs that we suggested, have since been used to test the predictions of my quantitative models. My results enabled us to understand the design principles for constructing a single structure, yet how competing structures assemble and maintain their sizes while sharing a common pool of building blocks remains an open question. Over the next five years, our goal is to quantitatively analyze the mechanisms used by the cell to share building blocks between competing structures. Proteins involved in disassembly of organelles offer a solution - in addition to disassembling pre-existing structures, they can provide key length-sensing feedback to the size of individual structures sharing a common pool of building blocks. Using simulation schemes and theoretical tools that I pioneered, we will identify discernible signatures of specific disassembly mechanisms, and quantitatively describe their repercussion on the sharing of common resources between different competing structures. Using actin structures and nucleolus as our model systems, we will design theory-driven experiments to verify our predictions with already established collaborations, and use experimentally tunable knobs to discriminate between different mechanisms that cells use to share building blocks between competing structures. A quantitative understanding of molecular mechanisms affecting organelle growth will accelerate the development of new therapies to combat many human neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (abnormalities in actin assembly) and Parkinson’s and Alzheimer’s disease (nucleolus abnormalities).