Nonequilibrium physics of signaling and spatial organization at the cellular scale

细胞尺度信号传导和空间组织的非平衡物理学

• 批准号: RGPIN-2021-03431
• 负责人: Brown, Aidan
• 金额: $ 1.75万
• 依托单位: Ryerson University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=762421
• 关键词: Nonequilibrium; physics; signaling; spatial; organization

Background The Second Law of Thermodynamics tells us that without energy input, any system will tend towards becoming disordered. For the basic units of life, biological cells, much of the energy consumed is not stored or used to build structures, but is dissipated to pay the cost of maintaining order by directing and coordinating cellular processes. Biological cells are also organized into spatial compartments of a variety of shapes and sizes that have distinct functional roles. The geometry (shape and size) of these compartments changes with health, prevailing conditions, and cell activities, indicating that these compartment geometries are important to biological function. Although a cell may appear relatively static, its constituent molecules and the structures they compose are very dynamic, continuously moving and changing. My long-term objectives are to understand how these cellular dynamics are driven by energy expenditure and influenced by geometry to achieve the many tasks that make a cell alive. This includes probing the physical limits placed by energy consumption and geometric confinement on important cellular processes. Objectives I will use theoretical and computational techniques to work towards three specific short-term objectives: 1) Understand how energy is used by cells to make decisions, such as by labelling cellular components for recycling. How is energy used to influence the dynamic addition and removal of these label molecules to decide to recycle a component at the right time? 2) Develop a quantitative framework for how cells control the spatial distribution of proteins. Cells are able to put specific protein types into certain compartments, without the proteins `knowing' where to go. How do cells spend energy and use geometry to ensure proteins are present where they are needed? 3) Understand how confining proteins to the narrow interiors of cellular compartments affects how signals can be generated within these compartments. Signaling often involves protein clustering or a phase transition in behaviour. How are clustering, phase transitions, and reaction kinetics impacted by geometric confinement to compartment interiors, and what limits does this put on signaling? Impact My research program, which provides valuable training to young scientists and quantitative skillsets for the modern workforce, uses theoretical approaches to understand the physical factors behind the operation of biological cells. This work pushes forward our understanding of the nonequilibrium nature of the mechanisms and rules underlying life, and has potential long term practical application to medicine. Alzheimer's disease, diabetes, and many other human pathologies are thought to originate at the cellular level, and understanding how cells carry out their function and remain healthy is essential to countering disease symptoms and causes.

背景热力学的第二定律告诉我们，如果没有能量输入，任何系统都会倾向于变得无序。对于生命的基本单位，生物细胞，大部分消耗的能量并未存储或用于建造结构，而是通过指导和协调蜂窝过程来消耗以支付维持秩序的成本。生物细胞也被组织成具有不同功能作用的各种形状和大小的空间室。这些隔室的几何形状（形状和大小）随着健康，主要条件和细胞活动而变化，表明这些隔室几何形状对生物学功能很重要。尽管细胞可能看起来相对静态，但其组成分子及其组成的结构非常动态，不断移动和变化。我的长期目标是了解这些细胞动力学是如何由能量消耗驱动的，并受到几何形状的影响，以实现使细胞活着的许多任务。这包括探测重要细胞过程上能耗和几何限制所带来的物理极限。目的我将使用理论和计算技术来实现三个特定的短期目标：1）了解细胞如何使用能量来做出决策，例如通过标记用于回收的细胞组件。如何使用能量来影响这些标签分子的动态添加和去除以决定在正确的时间回收组件？ 2）开发一个定量框架，用于细胞如何控制蛋白质的空间分布。细胞能够将特定的蛋白质类型放入某些隔室，而无需蛋白质“知道”去哪里。细胞如何花能量并使用几何形状来确保存在需要的蛋白质？ 3）了解将蛋白限制在细胞隔室狭窄内部的内部如何影响这些隔室内如何产生信号。信号传导通常涉及蛋白质聚类或行为中的相变。聚类，相变和反应动力学如何受到隔室内饰的几何影响，这对信号传导有什么限制？影响我的研究计划，该计划为年轻的科学家提供了宝贵的培训，并为现代劳动力提供了定量技能，它使用理论方法来了解生物细胞运行的物理因素。这项工作推动了我们对生命基本机制和规则非平衡性质的理解，并具有潜在的长期实际应用。人们认为阿尔茨海默氏病，糖尿病和许多其他人类病理源于细胞水平，并了解细胞如何发挥其功能并保持健康对于反疾病症状和原因至关重要。