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

在其构件共享池中生长的细胞器尺寸控制的设计原理

• 批准号: 10501369
• 负责人: Lishibanya Mohapatra
• 金额: $ 35.51万
• 依托单位: ROCHESTER INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-10 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501369
• 关键词: Actins; Affect; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Biochemical; Biological Models; Cell Nucleolus; Cells; Characteristics; Collaborations; Development; Disease; Feedback; Goals; Growth; Human; Individual; Length; Mathematical Model Simulation; Mediating; Modeling; Molecular; Neurodegenerative Disorders; Organelles; Parkinson Disease; Proteins; Research; Resources; Running; Scheme; Shapes; Structure; Techniques; Testing; Work; combat; design; experimental study; high dimensionality; novel therapeutics; programs; simulation; theories; tool

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).

摘要 活细胞含有各种可区分的部分，称为细胞器，其具有特征性的大小和大小。 具体功能。这些细胞器在各自的构建块的共享池中生长，并且非常明显地 能够保持它们的结构，尽管它们的构建块快速交换。这就引出了一个问题： 细胞器的大小是否在一个由细胞主动控制的共享构建模块池中生长？年的 生物化学实验已经揭示了与这些结构有关的过多的蛋白质，然而，由于 所涉及的变量的高维性，它们如何一起工作以创建适当大小的细胞器， 仍然没有很好地理解。因此，数学建模和模拟提供了一个令人兴奋的途径来解决 这些问题，与额外的好处，确定关键可调旋钮的生物化学家运行精简 实验在过去的几年里，使用这些技术对细胞器，如肌动蛋白电缆和鞭毛，我 确定了一个负反馈的大小，介导的减少池的积木或关键配件 细胞器特有的蛋白质，在控制生长中的细胞器的大小方面至关重要。重要的是，关键 我们建议的实验旋钮，已经被用来测试我的定量模型的预测。 我的研究结果使我们能够理解构建单一结构的设计原则， 结构组装并保持其大小，同时共享构建块的公共池仍然是开放的 问题未来五年，我们的目标是定量分析细胞用于共享的机制 竞争结构之间的构建块。参与细胞器分解的蛋白质提供了一个解决方案- 除了拆卸预先存在的结构，它们还可以提供键长度传感反馈， 共享构建块的公共池的各个结构。使用模拟方案和理论工具 我们将识别特定拆卸机制的可识别特征，并定量地 描述它们对不同竞争结构之间共享共同资源的影响。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理论。 预测与已经建立的合作，并使用实验可调旋钮来区分 细胞在竞争结构之间共享构建模块的不同机制之间的差异。一 对影响细胞器生长的分子机制的定量理解将加速细胞器的发展， 新的治疗方法，以打击许多人类神经退行性疾病，如肌萎缩侧索硬化症 （肌动蛋白组装异常）和帕金森病和阿尔茨海默病（核仁异常）。