CAREER: Modeling the Physical Regulation of Immune Cell Activation

该职业奖将建立一个综合研究和教育计划，利用理论和计算来阐明调节免疫细胞激活的物理机制。T细胞和B细胞等免疫细胞在寻找病原体的分子特征时，使用表面受体直接与其他细胞接触。一个新兴的免疫学范式是，在细胞表面的力量调节抗原识别和细胞活化。了解T细胞和B细胞的抗原识别仍然是免疫学中最重要的未解决问题之一。该项目将有助于免疫学的基础认识，并为设计免疫调节材料和治疗方法提供机制指导。该项目将利用最近的一项倡议，通过让高中生和社区大学生参与主动学习模块，增加田纳西州拥有大学学位的人数。此外，一年级本科生将以物理生物学的新研讨会为目标，重点将放在吸引来自田纳西州阿巴拉契亚地区的学生上。这些努力将有助于招收新的学生进入科学和工程领域，并将使更多的学生接触到物理学和生物学的界面。所有的研究生都将参与教育活动。一名研究生将花时间在实验实验室里，由PI组织的研讨会将把理论家和实验家聚集在一起，探索免疫细胞的物理调节。该项目将研究对适当免疫反应至关重要的过程。它将解决膜和细胞骨架力如何与力依赖解离动力学耦合以影响T细胞受体的动力学，阐明增强B细胞区分和内化膜呈递抗原的能力的机械过程，并表征T细胞表面的动态膜突起如何影响抗原搜索过程。研究这些过程将产生一个新的计算框架，可用于解决免疫学和细胞生物力学中的其他新兴问题。抗原识别的许多物理特征很难通过实验探索，也没有系统研究其潜在机制的框架。该项目将通过开发计算和理论方法来解决这一差距，这些方法可以捕获细胞-细胞界面上重要的生物物理相互作用，包括随机受体-配体结合动力学、膜力学和肌动蛋白介导的膜作用力。这些方法对于理解抗原识别是必不可少的，因为它们允许系统地研究实验无法达到的物理特征。计算框架将产生可以通过实验验证的假设，从而在理论和实验之间提供反馈。细胞间受体介导的相互作用在生物学中无处不在，因此，本提案中开发的方法可用于研究远远超出免疫学的各种生物现象。该项目由物理和细胞学部的生命系统物理学项目以及分子和细胞生物科学部的系统和合成生物学集群共同支持。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。

This CAREER award will establish an integrated research and education program that uses theory and computation to elucidate physical mechanisms that regulate immune cell activation. Immune cells such as T cells and B cells use surface receptors to directly engage other cells as they search for molecular signatures of pathogens. An emerging paradigm in immunology is that forces at the cell surface regulate antigen recognition and cell activation. Understanding antigen recognition by T cells and B cells remains one of the most significant unresolved issues in immunology. This project will contribute to fundamental immunological understanding and provide mechanistic guidance for designing immuno-modulatory materials and therapies. The project will leverage a recent initiative to increase the number of Tennesseans with college degrees by engaging high school and community college students in active learning modules. Additionally, first-year undergraduates will be targeted with a new seminar on physical biology, and an emphasis will be placed on engaging students from Tennessee's Appalachian region. These efforts will help to recruit new students into science and engineering, and will expose a broad range of students to the interface of physics and biology. All research students will be involved in educational activities. A graduate student will spend time embedded in an experimental lab, and a workshop organized by the PI will bring theorists and experimentalists together to explore the physical regulation of immune cells. This project will investigate processes that are essential for a proper immune response. It will resolve how membrane and cytoskeletal forces couple with force-dependent dissociation kinetics to influence the dynamics of T cell receptors, elucidate mechanical processes that enhance the ability of B cells to discriminate between and internalize membrane-presented antigens, and characterize how dynamic membrane protrusions on the T cell surface impact the antigen search process. Investigating these processes will result in a new computational framework that can be used to address other emerging questions in immunology and cellular bio-mechanics. Many physical features of antigen recognition are difficult to explore experimentally, and there is no framework for systematically investigating the underlying mechanisms. This project will address this gap by developing computational and theoretical approaches that capture important biophysical interactions at cell-cell interfaces, including stochastic receptor-ligand binding kinetics, membrane mechanics, and actin-mediated forces on the membrane. Such approaches are essential for understanding antigen recognition, as they allow systematic investigation of physical features that are experimentally inaccessible. The computational framework will generate hypotheses that can be experimentally tested, thus providing feedback between theory and experiment. Receptor-mediated interactions between cells are ubiquitous in biology, and as such, the approaches developed in this proposal can be used to study diverse biological phenomena extending far beyond immunology. This project is being jointly supported by the Physics of Living Systems program in the Division of Physics and the Cellular Cluster and the Systems and Synthetic Biology clusters in the Division of Molecular and Cellular Biosciences.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.