Mechanics of T cell migration

T 细胞迁移机制

• 批准号: 10477331
• 负责人: Patrick William Oakes
• 金额: $ 39.19万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477331
• 关键词: Actins; Adhesions; Affect; Architecture; Behavior; Biological; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chemicals; Complex; Contracts; Coupled; Cues; Cytoskeleton; Engineering; Ensure; Environment; Equilibrium; Extracellular Matrix; Focal Adhesions; Future; Generations; Goals; Immune; Immune system; In Vitro; Individual; Integrins; Knowledge; Lead; Measurement; Measures; Mechanics; Mediating; Mesenchymal; Morphology; Myosin ATPase; Production; Property; Proteins; Role; Speed; Stress; Stress Fibers; T cell regulation; T-Lymphocyte; Testing; Th1 Cells; Th2 Cells; Time; Tissues; Traction; Traction Force Microscopy; cell motility; chemokine; cytokine; effector T cell; in vivo; live cell imaging; mechanical properties; mechanical signal; migration; physical property; polymerization

PROJECT SUMMARY/ABSTRACT – PROJECT 4 Migration is an essential component of a functional immune system. Responding to both chemical and mechanical signaling cues, cells need to move in complex environments including both within and between tissues. To accomplish this, cells need to generate internal forces which can be coupled to their surrounding matrix through adhesions. Both of these physical interactions must be delicately balanced in time and space to ensure motility. While this balance has been extensively explored in the context of mesenchymal cell migration, these relationships remain ill-defined in the amoeboid migration modes used by T cells and other immune cells. Our overall goal is to define the mechanical interactions that enable and guide immune cell migration. Chemokines, which stimulate the protrusion machinery, and integrins, which mediate adhesion, are thought to be the primary biological effectors of T cell migration. Mechanically, cytoskeletal dynamics consisting of actin polymerization and myosin contractility are the predominant mechanisms for generating forces in cells. The interplay of these components defines the motility of the cell. We hypothesize that the migration behaviors of different immune cells lie along a single continuum, differing only in their relative contributions of adhesion and force generation. We further speculate that effector programming leads to differences in the activation thresholds for these physical interactions that may modify the way distinct effector subsets respond to their physical microenvironment. To test this hypothesis, we propose to make precise mechanical measurements of the migration machinery and determine how they affect the migration efficiency of T cells in vitro. We will then use our in vitro findings as a basis to interpret similar morphological behaviors and interactions in the more complex in vivo inflamed tissue environment. Aim 1: To determine the relation between actin polymerization and traction stress in T cells. Aim 2: To determine how ECM composition, organization and material properties regulate adhesion in T cells. Aim 3: Do T cells adapt their migration behavior to the microenvironment in vivo? Our findings will elucidate the underlying mechanical mechanisms regulating T cell migration and can be used to develop new targets for future therapies.

项目摘要/摘要 – 项目 4 迁移是功能性免疫系统的重要组成部分，对化学物质和化学物质都有反应。 机械信号线索，细胞需要在复杂的环境中移动，包括内部和外部 为了实现这一点，细胞需要产生可以与其周围环境耦合的内力。 这两种物理相互作用必须在时间和空间上达到微妙的平衡。 虽然这种平衡已在间充质细胞迁移的背景下得到广泛探索， 在 T 细胞和其他免疫细胞使用的变形虫迁移模式中，这些关系仍然不明确。 我们的总体目标是定义促进和引导免疫细胞迁移的机械相互作用。 刺激突出机制的趋化因子和介导粘附的整合素被认为 是 T 细胞迁移的主要生物效应器，由肌动蛋白组成。 聚合和肌球蛋白收缩性是细胞中产生力的主要机制。 这些成分的相互作用决定了细胞的迁移行为。 不同的免疫细胞位于一个单一的连续体上，仅在粘附和粘附的相对贡献上有所不同 我们进一步推测效应器编程会导致激活差异。 这些物理相互作用的阈值可能会改变不同效应器子集对其响应的方式 为了检验这一假设，我们建议对物理微环境进行精确的机械测量。 然后我们将研究迁移机制并确定它们如何影响 T 细胞的体外迁移效率。 使用我们的体外研究结果作为基础来解释更多相似的形态行为和相互作用 目的1：确定肌动蛋白聚合之间的关系。 目标 2：确定 ECM 的组成、组织和材料特性。 目标 3：T 细胞是否会适应体内微环境的迁移行为？ 我们的研究结果将阐明调节 T 细胞迁移的潜在机械机制，并可用于 为未来的治疗开发新的靶点。