Forces, Kinetics, and the Thermodynamics of Crowded Cell Surfaces

拥挤细胞表面的力、动力学和热力学

• 批准号: 2150686
• 负责人: Sho Takatori
• 金额: $ 91.98万
• 依托单位: University of California-Santa Barbara
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2150686&HistoricalAwards=false
• 关键词: Forces; Kinetics; Thermodynamics; Crowded; Cell

The mammalian cell membrane is covered with a protective “shield” of proteins and sugars that enables cells to interact with their local environment. Important cell functions mediated by the cell membrane, like the delivery of growth factors and antibodies to cell surface receptors, requires these soluble species to penetrate through and interact within this thick shield that covers and protects the cell surface. The goal of this project is to develop a fundamental understanding of the physical organization of the proteins and sugars that make up the shield, and to identify the mechanisms of molecular transport and binding on the cell membrane. This will be achieved by studying the binding of one particular soluble species, a monoclonal antibody, on both live cells and on engineered synthetic surfaces. In addition to advancing a basic biophysical understanding of the cell membrane, this project may have significant broader impacts in biopharmaceutical drug discovery of antibody therapeutics that target diseased cell surfaces. The investigator’s research group will broaden STEM participation by integrating the proposed research with a two-part outreach program. First, the group will engage underrepresented groups with academic research, targeting junior transfer students to ease their transition to a four-year university and broaden their professional development. Second, the PI will teach effective science communication skills to students, which is an important skill that is largely missing in the traditional STEM curriculum. The objective of this project is to determine how the molecular organization of the cell surface glycocalyx modulates the biophysical interactions of proteins, polysaccharides, and macromolecules on the cell membrane. The project will combine coarse-grained molecular dynamics simulations, in-vitro reconstitution of engineered cell surfaces, and live cell experiments to provide a spatial and temporal description of the molecular-to-mesoscale surface interactions that govern plasma membrane organization. By quantifying the transport and binding of monoclonal antibodies to engineered antigen receptors with various chemical and physical properties, the project will determine the cooperative dynamics of multibody surface protein interactions. The project seeks to advance a quantitative framework to isolate the effects of protein glycosylation, density, charge, stiffness, and other biophysical properties on live plasma membranes. This project will determine surface protein interactions that cannot be obtained from studying purified proteins in isolation. Through the development of new tools and concepts, this project will advance the fundamental understanding of the cell membrane dynamics that govern a variety of surface-mediated cellular processes.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.

哺乳动物的细胞膜上覆盖着一层蛋白质和糖的保护性“盾牌”，使细胞能够与局部环境相互作用。细胞膜介导的重要细胞功能，如向细胞表面受体传递生长因子和抗体，需要这些可溶性物质穿透覆盖和保护细胞表面的厚屏蔽并相互作用。该项目的目标是对构成细胞膜的蛋白质和糖的物理组织有一个基本的了解，并确定细胞膜上分子运输和结合的机制。这将通过研究一种特殊的可溶性物质，一种单克隆抗体，在活细胞和工程合成表面上的结合来实现。除了促进对细胞膜的基本生物物理理解外，该项目可能对针对病变细胞表面的抗体疗法的生物制药药物发现具有重要的广泛影响。研究者的研究小组将通过将拟议的研究与两部分外展计划相结合来扩大STEM的参与。首先，该小组将让代表性不足的群体参与学术研究，以大三转学生为目标，帮助他们轻松过渡到四年制大学，拓宽他们的专业发展。其次，PI将向学生传授有效的科学沟通技巧，这是传统STEM课程中很大程度上缺失的重要技能。该项目的目的是确定细胞表面糖萼的分子组织如何调节细胞膜上蛋白质、多糖和大分子的生物物理相互作用。该项目将结合粗粒度的分子动力学模拟、工程细胞表面的体外重构和活细胞实验，提供控制质膜组织的分子到中尺度表面相互作用的空间和时间描述。通过量化单克隆抗体与具有各种化学和物理性质的工程抗原受体的运输和结合，该项目将确定多体表面蛋白相互作用的合作动力学。该项目旨在推进一个定量框架，以分离蛋白质糖基化、密度、电荷、硬度和其他生物物理特性对活质膜的影响。该项目将确定表面蛋白的相互作用，而这些相互作用是无法从分离的纯化蛋白中获得的。通过开发新的工具和概念，该项目将促进对控制各种表面介导的细胞过程的细胞膜动力学的基本理解。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Active Surface Flows Accelerate the Coarsening of Lipid Membrane Domains

活性表面流加速脂质膜域的粗化

• DOI: 10.1103/physrevlett.131.128402
• 发表时间: 2023
• 期刊: Physical Review Letters
• 影响因子: 8.6
• 作者: Arnold, Daniel P.;Gubbala, Aakanksha;Takatori, Sho C.
• 通讯作者: Takatori, Sho C.

Enhanced dispersion in an oscillating array of harmonic traps

增强谐波陷阱振荡阵列中的色散

• DOI: 10.1103/physreve.107.014601
• 发表时间: 2023
• 期刊: Physical Review E
• 影响因子: 2.4
• 作者: Barakat, Joseph M.;Takatori, Sho C.
• 通讯作者: Takatori, Sho C.