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).

抽象的 活细胞包含各种可区分的零件，称为细胞器，这些零件具有特征大小和 特定功能。这些细胞器在各自的构件的共享池中生长，并且非常明显 可以将其结构目的地迅速交换，以迅速交换其构建基块。这提示了一个问题：如何 在共享的构建块中生长的细胞器大小是否由细胞积极控制？年 生化实验揭示了与这些结构有关的大量蛋白质，但是由于 所涉及的变量的高维度，它们如何共同创建适当大小的细胞器是 仍然不太了解。因此，数学建模和模拟为解决方案提供了令人兴奋的途径 这些问题，其额外的好处是识别关键可调节旋钮，以使生物化学家简化地运行 实验。在过去的几年中，使用这些技术在肌动蛋白电缆和鞭毛等细胞器上，我 确定对大小的负面反馈是由构建块或钥匙配件池减少介导的 特定于细胞器的蛋白质对于控制生长细胞器的大小至关重要。重要的是，关键 我们建议的实验旋钮已被用来测试我的定量模型的预测。 我的结果使我们能够理解构建单个结构的设计原则，但如何竞争 结构组装和保持大小，同时共享一个共同的构建基库仍然是开放的 问题。在接下来的五年中，我们的目标是定量分析细胞共享的机制 竞争结构之间的组成部分。参与细胞器拆卸的蛋白质提供了解决方案 - 除了拆卸预先存在的结构外，它们还可以为大小提供关键的长度反馈 各个结构共享一个共同的构建基库。使用模拟方案和理论工具 我率先进行，我们将确定特定拆卸机制的可辨认签名，并定量 描述他们对不同竞争结构之间共同资源共享的影响。使用 肌动蛋白结构和核仁作为我们的模型系统，我们将设计以理论驱动的实验来验证我们的 通过已经建立的合作进行预测，并使用实验可调的旋钮来区分 在竞争结构之间用于共享构件的不同机制之间。一个 对影响细胞器生长的分子机制的定量理解将加速发展 抗击许多人类神经退行性疾病（如肌萎缩性侧索硬化症）的新疗法 （肌动蛋白组装异常），帕金森氏症和阿尔茨海默氏病（核仁异常）。