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.

所有级别的标准生物学教科书都说明，细胞膜覆盖着细胞内不同的隔间，所有令人惊叹的化学过程都发生在那里，使生命成为可能。然而，现在很明显，细胞内部有一个更丰富的结构，提供了更多和不依赖于膜的方式来重组细胞成分，从而使细胞功能得以实现。特别是，近年来人们认识到，细胞蛋白质的单个水相可以转变为两个不同的相，通常是悬浮在蛋白质稀溶液中的富含蛋白质的液滴的相，即发生液-液相分离，类似于水中的油滴。已经对动物、细菌和植物细胞进行了这种行为的观察。因此，这些所谓的无膜室，或生物分子凝聚体，是重要的特征，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联系在一起。溶液的物理化学，包括电解质浓度和离子类型、pH和渗透强度，可以决定这些溶液性质变化的性质和规模，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，两者结合使用，以更好地表征和了解这些生物分子凝聚物的物理化学特征，包括它们如何与附近的表面，如膜相互作用。此外，这个项目将为本科生和研究生提供支持和研究机会。细胞环境中蛋白质的液-液相分离(LLP)和相关的相变最近被认为是活细胞中形成无膜室或生物分子凝聚体的一般机制。生物凝聚物流动和年龄，这已被认为是相互联系的细胞的化学和机械反应。因此，最近的研究提供了对蛋白质溶液的流变性的测量，包括近似粘度、表面张力，因为它们与细胞质不相容，以及用于粘弹性表征的松弛时间。盐浓度会影响聚合物的构象，从而影响凝析油的流变性和表面张力，还可能影响凝析油润湿基材的方式。该项目的研究将开发连续介质粘弹性模型，与聚合物物理文献相似，以解决与生物凝聚物流动和润湿相关的问题，包括它们在表面(膜、微管等)上的行为；该方法将识别凝析油特有的微观结构变量，并解决细胞质成分重排的重要数学问题。这项工作将在物理化学流体力学的框架内包括静电和电动效应，以解释影响细胞流动的凝析油的独特特征。因此，通过三个相互关联的研究主题，我们将为生物凝析油的动力学提供一个数学框架，从(1)应力-应变和应变率行为的本构建模，到(2)模型流动的模拟，以及(3)测试这些描述的实验。结果将在对实验学家和生物学家有用的水平上提供，并在数学水平上始终如一地整合软材料响应的热力学、力学和物理化学。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。