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: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=742538
• 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.

背景热力学第二定律告诉我们，如果没有能量输入，任何系统都将趋于无序。对于生命的基本单位，生物细胞，所消耗的大部分能量不是存储或用于建造结构，而是通过指导和协调细胞过程来分散以支付维持秩序的成本。生物细胞也被组织成各种形状和大小的空间隔间，具有不同的功能作用。这些隔室的几何形状(形状和大小)随着健康、流行条件和细胞活动的变化而变化，表明这些隔室的几何形状对生物功能很重要。尽管细胞可能看起来相对静态，但它的组成分子和它们组成的结构是非常动态的，不断地移动和变化。我的长期目标是了解这些细胞动力学是如何受到能量消耗的驱动和几何结构的影响来完成使细胞活着的许多任务的。这包括探索能量消耗和几何限制对重要细胞过程施加的物理限制。目标我将使用理论和计算技术来努力实现三个具体的短期目标：1)了解细胞如何利用能量做出决定，例如通过标记细胞组件进行回收。如何利用能量来影响这些标记分子的动态添加和移除，以决定在正确的时间回收成分？2)为细胞如何控制蛋白质的空间分布开发一个量化框架。细胞能够将特定类型的蛋白质放入特定的隔间，而不需要蛋白质“知道”去哪里。细胞如何消耗能量并利用几何构型来确保蛋白质存在于需要它们的地方？3)了解将蛋白质限制在细胞隔间狭窄的内部是如何影响这些隔间内信号产生的。信号传递通常涉及蛋白质聚集或行为的相变。几何限制对隔室内部的聚集、相变和反应动力学有何影响？这对信号有什么限制？Impact My研究计划为年轻科学家提供宝贵的培训，为现代劳动力提供定量技能，使用理论方法来了解生物细胞运行背后的物理因素。这项工作推动了我们对生命机制和规则的非平衡性的理解，并具有潜在的长期实际应用于医学。阿尔茨海默氏症、糖尿病和许多其他人类病理被认为起源于细胞水平，了解细胞如何执行其功能并保持健康对于对抗疾病症状和原因至关重要。