Mechanisms of Immune Cell Response to Mechanical Load

免疫细胞对机械负荷的反应机制

• 批准号: 1563355
• 负责人: Arpita Upadhyaya
• 金额: $ 40万
• 依托单位: University of Maryland, College Park
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1563355&HistoricalAwards=false
• 关键词: Mechanisms; Immune; Cell; Response; Mechanical

Cells have the remarkable ability to sense and respond to the mechanical properties of their environment. This mechanosensing ability is essential for many phenomena ranging from the movement of individual cells, cell differentiation and fate choice as well as large-scale tissue rearrangement during development. Recent work has shown that immune cells are responsive to their mechanical environment and this mechanosensitivity tunes their ability to respond to infectious agents. This project aims to understand how internal forces generated by the biopolymer networks of actin filaments and the motor protein, myosin, enable the T lymphocyte to modulate biochemical signaling, enhancing our understanding of how mechanical stimuli and biochemical signaling are coupled during the immune response using concepts and tools from physics and engineering. This work has potential implications for improving the design of artificial antigen-presenting devices that can enhance the efficiency of immunotherapies against pathogens and tumors. The PI will develop a lecture and laboratory course in cell mechanics, in which concepts from topics such as statistical and continuum mechanics will be used to explain biological processes. The PI will encourage minority and high school students from the area to participate in research. The PI will organize biophysics laboratory demonstrations as part of the Summer Girls Program at the University of Maryland to encourage participation of female students in science and technology fields. The binding of T cell receptors (TCRs) to antigen-derived peptides results in the formation of dynamic protein assemblies, called signaling microclusters, that serve as the initiating points for T cell activation and the first step of the adaptive immune response. Recent work has revealed that T cells are responsive to the mechanical environment on which antigens are presented and that physical forces can trigger T cell activation. However, the mechanisms by which T cells combine mechanical and biochemical signals to carry out specific functions is not well understood. This project will test the hypothesis that signaling microclusters are responsive to forces, acting as dynamic mechanosensors, thereby allowing the cell to respond and sense the physical properties of the antigen-bearing surface. The PI aims to elucidate how cellular forces regulate the assembly of signaling assemblies at activated T cell receptors (Aim 1), to determine the molecular linkages between cytoskeletal forces and T cell signaling activation (Aim 2) and how these forces more globally lead to activation at the level of the whole cell (Aim 3). This study will reveal common principles in the mechanisms of receptor-mediated sensing of the mechanical environment and the more commonly studied integrin-mediated mechanosensing.

细胞具有感知和响应环境机械特性的非凡能力。这种机械传感能力对于许多现象至关重要，包括单个细胞的运动、细胞分化和命运选择以及发育过程中的大规模组织重排。最近的研究表明，免疫细胞对其机械环境有反应，这种机械敏感性调整了它们对传染源的反应能力。该项目旨在了解肌动蛋白丝和运动蛋白肌球蛋白的生物聚合物网络产生的内力如何使 T 淋巴细胞调节生化信号传导，从而利用物理和工程学的概念和工具增强我们对免疫反应过程中机械刺激和生化信号传导如何耦合的理解。这项工作对于改进人工抗原呈递装置的设计具有潜在的意义，该装置可以提高针对病原体和肿瘤的免疫疗法的效率。 PI 将开发细胞力学讲座和实验课程，其中统计和连续介质力学等主题的概念将用于解释生物过程。 PI 将鼓励该地区的少数民族和高中生参与研究。作为马里兰大学暑期女生项目的一部分，PI 将组织生物物理实验室演示，以鼓励女学生参与科学和技术领域。 T 细胞受体 (TCR) 与抗原衍生肽的结合导致动态蛋白质组装体的形成，称为信号微簇，作为 T 细胞激活的起始点和适应性免疫反应的第一步。最近的研究表明，T 细胞对抗原呈递的机械环境有反应，并且物理力可以触发 T 细胞激活。然而，T 细胞结合机械和生化信号来执行特定功能的机制尚不清楚。该项目将测试信号微簇对力有反应的假设，充当动态机械传感器，从而使细胞能够响应并感知抗原承载表面的物理特性。该 PI 旨在阐明细胞力如何调节激活的 T 细胞受体上信号组件的组装（目标 1），确定细胞骨架力与 T 细胞信号传导激活之间的分子联系（目标 2），以及这些力如何更全面地导致整个细胞水平的激活（目标 3）。这项研究将揭示受体介导的机械环境传感机制和更常研究的整合素介导的机械传感机制的共同原理。