Nonequilibrium physics of signaling and spatial organization at the cellular scale

热力学第二定律告诉我们，没有能量输入，任何系统都会趋于无序。对于生命的基本单位——生物细胞来说，消耗的大部分能量并没有被储存起来或用于构建结构，而是被消耗掉，通过指导和协调细胞过程来支付维持秩序的费用。生物细胞也被组织成各种形状和大小的空间隔间，具有不同的功能角色。这些隔室的几何形状（形状和大小）随着健康、普遍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。虽然一个细胞可能看起来相对静止，但它的组成分子和它们组成的结构是非常动态的，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受到能量消耗和几何形状的影响，从而实现使细胞存活的许多任务。这包括探索能量消耗和重要细胞过程的几何限制所带来的物理限制。我将使用理论和计算技术来实现三个具体的短期目标：1)了解细胞如何使用能量来做出决定，例如通过标记细胞成分进行回收。如何使用能量来影响这些标签分子的动态添加和移除，以决定在正确的时间回收一个组件？2)建立细胞如何控制蛋白质空间分布的定量框架。细胞能够将特定类型的蛋白质放入特定的隔室，而这些蛋白质不知道要去哪里。细胞如何消耗能量并利用几何结构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信号在这些隔间内产生的。信号通常涉及蛋白质聚集或行为的相变。聚类、相变和反应动力学如何受到隔间内部几何限制的影响，这对信号传导有什么限制？我的研究项目为年轻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，它使用理论方法来理解生物细胞运作背后的物理因素。这项工作推动了我们对生命机制和规则的非平衡性质的理解，并有潜在的长期实际应用于医学。阿尔茨海默病、糖尿病和许多其他人类疾病被认为起源于细胞水平，了解细胞如何发挥其功能并保持健康对于对抗疾病症状和病因至关重要。

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.