Forces, Kinetics, and the Thermodynamics of Crowded Cell Surfaces

哺乳动物的细胞膜上覆盖着一层由蛋白质和糖组成的保护性“盾牌”，使细胞能够与当地环境相互作用。由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，需要这些可溶性物种穿透并相互作用于覆盖和保护细胞表面的厚盾牌。这个项目的目标是对构成屏蔽层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定的可溶性物种--单抗--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了解外，该项目还可能在生物制药药物发现针对病变细胞表面的抗体疗法方面产生重大而广泛的影响。研究人员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，该组织将让代表不足的群体进行学术研究，目标是初级转学学生，以方便他们过渡到四年制大学，并拓宽他们的专业发展。其次，PI将向学生传授有效的科学交流技能，这是传统STEM课程中基本上缺失的一项重要技能。该项目的目标是确定细胞表面糖基化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分子动力学模拟、工程细胞表面的体外重建和活细胞实验，提供支配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。通过量化单抗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。该项目旨在提出一个定量框架，以分离蛋白质糖基化、密度、电荷、硬度和其他生物物理性质对活的质膜的影响。这个项目将确定从分离纯化的蛋白质中无法获得的表面蛋白质相互作用。通过开发新的工具和概念，该项目将促进对管理各种表面介导的细胞过程的细胞膜动力学的基本了解。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.