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一个共同方面，无论病因如何，其调控是本提案的主题。迁移依赖于细胞产生的牵引力，并施加于底层的细胞外基质。这些力的精细调节对于最佳的细胞迁移是必不可少的，因为不足或过度的力会减缓或阻止移动。牵引力的调节，特别是与白细胞有关的牵引力的调节，是复杂的，人们对其知之甚少。组织内细胞的机械感知是指细胞感知其环境中机械特性差异的能力。环境的物理性质已被证明影响许多细胞类型的基因表达、增殖、细胞骨架组织和存活。相对而言，中性粒细胞的宿主防御功能很少发生在循环细胞或非粘附细胞中，也不会发生在塑料或玻璃等坚硬的表面上。本提案中的实验将检查中性粒细胞在基质上的功能，这些基质具有生理相关的刚度，因为它们被设计成模仿大多数组织中发现的弹性范围。据推测，中性粒细胞解释了底层基质的机械刚度，并对迁移过程中牵引力的时空调节变化做出了反应。进一步假设，牵引力调节也是迁移细胞所暴露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意义，如与宿主防御相关的呼吸爆发和吞噬。细胞表面整合素被认为可以将机械和生化信号转导成最终决定中性粒细胞形状和功能的细胞骨架改变。

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.