DMS/NIGMS 1: Viscoelasticity and Flow of Biological Condensates via Continuum Descriptions - How Droplets Coalesce and Wet Cellular Surfaces

DMS/NIGMS 1：通过连续体描述的生物凝聚物的粘弹性和流动 - 液滴如何聚结和润湿细胞表面

• 批准号: 2245850
• 负责人: Howard Stone
• 金额: $ 60万
• 依托单位: Princeton University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2245850&HistoricalAwards=false
• 关键词: DMS; NIGMS; Viscoelasticity; Flow; Biological

Standard textbooks in biology, at all levels, illustrate that membranes cover the distinct compartments inside cells, where all the amazing chemical processing occurs that makes life possible. However, it is now apparent that the cell interior has a richer structure that provides for more and membrane-independent ways to reorganize cellular components and thus enable cellular functions. In particular, in recent years it has been recognized that a single aqueous phase of cellular proteins can transition into two distinct phases, typically a phase of liquid droplets rich in protein suspended in a dilute solution of proteins, i.e., liquid-liquid phase separation occurs, comparable to oil droplets in water. Observations of this behavior have been made for animal, bacterial, and plant cells. Consequently, these so-called membrane-less compartments, or biomolecular condensates, are important to characterize since they help explain fundamental cell biology and are starting to be linked to possible disease states. The physical chemistry of the solution, including the electrolyte concentration and ion type, pH, and osmotic strength, can dictate the nature and scale of these changes in solution properties and so influence cell function, or dysfunction. The research in this project includes both experiments and theory, used together, to better characterize and understand the physicochemical features of these biomolecular condensates including how they interact with nearby surfaces, such as membranes. In addition, this project will provide support and research opportunities for undergraduate and graduate students.Liquid-liquid phase separation (LLPS) and related phase transitions of proteins in the cellular milieu were recognized recently as a generic mechanism in living cells for the formation of membrane-less compartments, or biomolecular condensates. Biological condensates flow and age, which has been suggested to interrelate the chemical and mechanical responses of the cell. Consequently, recent studies have provided measurements of the rheology of the protein solutions, including approximate viscosities, surface tension, because they are immiscible with the cytoplasm, and relaxation times for the viscoelastic characterization. Salt concentration, because it influences the polymer conformation, affects the rheological response and surface tension of the condensates and may also influence how the condensates wet a substrate. The research in this project will develop continuum viscoelastic models, familiar from the polymer physics literature, to address questions associated with flow and wetting of biological condensates, including their behavior on surfaces (membranes, microtubules, etc.); the approach will recognize the microstructural variables specific to condensates and address important mathematical questions of rearrangements of cytoplasmic components. The work will include electrostatic and electrokinetic effects within the framework of physicochemical hydrodynamics to account for unique features of condensates that impact cellular flows. Thus, via three interconnected research themes, we will provide a mathematical framework for dynamics of biological condensates, from (1) constitutive modeling of the stress versus strain and strain rate behavior, to (2) simulations of model flows, and (3) experiments testing these descriptions. The results will be given both at a level useful to an experimentalist and biologist and at a mathematical level that consistently integrates the thermodynamics, mechanics, and physical chemistry of soft material responses.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在各个层面上，生物学的标准教科书都说明了膜覆盖了细胞内部的不同隔室，其中所有令人惊叹的化学加工都会发生使生命成为可能。但是，现在很明显，细胞内部具有更丰富的结构，可提供更多和膜独立的方式来重新组织细胞成分，从而启用细胞功能。特别是，近年来，人们已经认识到，细胞蛋白的单个水相可以过渡为两个不同的阶段，通常是一个液滴的相位，富含蛋白质的液滴阶段，这些液滴悬浮在稀释的蛋白质溶液中，即液态液相分离，与水中的油滴相当。已经对动物，细菌和植物细胞进行了这种行为的观察。因此，这些所谓的无膜隔室或生物分子冷凝物对于表征很重要，因为它们有助于解释基本的细胞生物学，并开始与可能的疾病状态有关。溶液的物理化学性质，包括电解质浓度和离子类型，pH和渗透强度，可以决定溶液特性中这些变化的性质和尺度，从而影响细胞功能或功能障碍。该项目的研究包括实验和理论，共同使用，以更好地表征和理解这些生物分子冷凝水的理化特征，包括它们与附近表面（例如膜）的相互作用。此外，该项目将为本科生和研究生提供支持和研究机会。液体 - 液相分离（LLP）和蛋白质中蛋白质中蛋白质的相关相变，最近被认为是活细胞中无膜隔室或生物分子冷凝物形成的生物细胞中的一种通用机制。生物冷凝水的流量和年龄，已建议将细胞的化学和机械反应相互关联。因此，最近的研究提供了对蛋白质溶液的流变学的测量，包括近似粘度，表面张力，因为它们与细胞质不混乱，以及用于粘弹性表征的松弛时间。盐浓度由于影响聚合物构象，会影响冷凝水的流变反应和表面张力，并且也可能影响冷凝水湿润的底物。该项目中的研究将开发连续的粘弹性模型，从聚合物物理学文献中熟悉，以解决与生物冷凝物的流动和润湿有关的问题，包括它们在表面上的行为（膜，微管等）；该方法将识别特定于冷凝水的微观结构变量，并解决细胞质成分重排的重要数学问题。这项工作将包括物理化学流体动力学框架内的静电和电动效应，以说明影响细胞流量的冷凝物的独特特征。因此，通过三个相互联系的研究主题，我们将提供一个数学框架，用于生物冷凝物动力学的数学框架，从（1）应力与应变率和应变速率行为的组成型建模到（2）模型流的模拟以及（3）测试这些描述的实验。结果将以对实验主义者和生物学家有用的水平以及数学水平有用，并始终如一地整合软材料反应的热力学，力学和物理化学。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子和更广泛影响的评估来通过评估来支持的，这是值得的。