Neutrophil Mechanosensing

描述(由申请人提供)：中性粒细胞迁移是所有炎症反应的共同方面，无论其病因如何，其调节是本提案的主题。迁移依赖于细胞产生并施加在底层细胞外基质上的牵引力。对这些力量的精细调控对于最佳细胞迁移是至关重要的，因为力量不足或过大都会减缓或阻碍细胞的移动。牵引力的调节，特别是当它们与白细胞有关时，是复杂的，也是鲜为人知的。组织内细胞的机械感应是指细胞感知其环境机械特性差异的能力。环境的物理性质已被证明影响多种细胞类型中的基因表达、增殖、细胞骨架组织和生存。中性粒细胞的宿主防御功能相对较少发生在循环细胞或非贴壁细胞中，也不会出现在像塑料或玻璃这样坚硬的表面。这项提议中的实验将检查具有生理相关硬度的底物上的中性粒细胞功能，因为它们被设计成模拟大多数组织中的弹性范围。假设中性粒细胞解释了底层基质的机械硬度，并对迁移过程中牵引力的空间和时间调节做出反应。进一步假设，牵引力调节也是迁移细胞接触到的细胞外基质配体的功能。研究还将确定机械信号对其他中性粒细胞功能的重要性，如与宿主防御相关的呼吸爆发和吞噬作用。细胞表面整合素被认为可以将机械信号和生化信号转化为细胞骨架的改变，最终决定中性粒细胞的形态和功能。 与公共卫生相关炎症是对伤害或感染的一种基本反应，因为它防止感染蔓延并开始愈合过程。白细胞在血液中持续循环，但对局部损伤部位的反应是，它们必须离开血液，在受损组织中迁移，才能开始愈合。迁移依赖于细胞产生并施加在底层细胞外基质上的牵引力。组织内细胞的机械感应是指细胞感知其环境机械特性差异的能力。环境的物理性质已被证明影响多种细胞类型中的基因表达、增殖、细胞骨架组织和生存。中性粒细胞的宿主防御功能相对较少，发生在循环或非贴壁细胞中，也不会出现在像塑料或玻璃这样坚硬的表面上，而这些表面是最常用于实验的表面。这项提议中的实验将检查具有生理相关硬度的底物上的中性粒细胞功能，因为它们被设计成模拟大多数组织中的弹性范围。

DESCRIPTION (provided by applicant): Neutrophil migration is a common aspect of all inflammatory responses, regardless of etiology, and its regulation is the subject of this proposal. Migration relies on tractional forces generated by the cell and exerted onto the underlying extracellular matrix. The fine regulation of these forces is essential for optimal cell migration as insufficient or excessive force will slow or prevent mobility. The regulation of tractional forces, particularly as they pertain to leukocytes, is complex and poorly understood. Mechanosensing of cells within tissues refers to the ability of the cell to perceive differences in the mechanical properties of its environment. The physical nature of the environment has been shown to influence gene expression, proliferation, cytoskeletal organization and survival in a number of cell types. Relatively few host defense functions of neutrophils take place in circulating or nonadherent cells, nor do they occur on surfaces as rigid as plastic or glass. Experiments in this proposal will examine neutrophil functions on substrata that are of physiologically relevant stiffnesses as they are designed to mimic the range of elasticity found in most tissues. It is hypothesized that neutrophils interpret the mechanical stiffness of an underlying substrate and respond with changes in the spacial and temporal regulation of traction forces during migration. It is hypothesized further that traction force regulation is also a function of the extracellular matrix ligands to which migrating cells are exposed. Studies will also determine the significance of mechanical signals on other neutrophil functions, such as respiratory burst and phagocytosis that are relevant to host defense. Cell surface integrins are proposed to transduce both mechanical and biochemical signals into cytoskeletal alterations that ultimately determine neutrophil shape and function. PUBLIC HEALTH RELEVANCE Inflammation is an essential response to injury or infection as it prevents infections from becoming widespread and begins the process of healing. White blood cells (leukocytes) circulate continuously in the bloodstream but in response to a local site of injury, they must leave the blood and migrate through the damaged tissue to begin healing. Migration relies on tractional forces generated by the cell and exerted onto the underlying extracellular matrix. Mechanosensing of cells within tissues refers to the ability of the cell to perceive differences in the mechanical properties of its environment. The physical nature of the environment has been shown to influence gene expression, proliferation, cytoskeletal organization and survival in a number of cell types. Relatively few host defense functions of neutrophils, take place in circulating or nonadherent cells, nor do they occur on surfaces as rigid as plastic or glass which are the surfaces that are most often used for experiments. Experiments in this proposal will examine neutrophil functions on substrata that are of physiologically relevant stiffnesses as they are designed to mimic the range of elasticity found in most tissues.