Neutrophil Mechanosensing

描述（由申请人提供）：无论病因如何，中性粒细胞迁移是所有炎症反应的共同方面，其调节是本提案的主题。迁移依赖于细胞产生并施加到下面的细胞外基质上的牵引力。这些力的精细调节对于最佳细胞迁移至关重要，因为力不足或过度会减慢或阻止细胞迁移。牵引力的调节，特别是与白细胞相关的调节，是复杂且知之甚少的。组织内细胞的机械传感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会影响多种细胞类型的基因表达、增殖、细胞骨架组织和存活。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，也不会发生在塑料或玻璃等刚性表面上。该提案中的实验将检查具有生理相关硬度的基质上的中性粒细胞功能，因为它们旨在模拟大多数组织中发现的弹性范围。据推测，中性粒细胞解释底层基质的机械刚度，并对迁移过程中牵引力的空间和时间调节的变化做出反应。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重要性，例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和生化信号转导为细胞骨架的改变，最终决定中性粒细胞的形状和功能。 公共卫生相关性炎症是对损伤或感染的重要反应，因为它可以防止感染广泛传播并开始愈合过程。白细胞（白细胞）在血流中持续循环，但为了响应局部损伤部位，它们必须离开血液并迁移通过受损组织才能开始愈合。迁移依赖于细胞产生并施加到下面的细胞外基质上的牵引力。组织内细胞的机械传感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会影响多种细胞类型的基因表达、增殖、细胞骨架组织和存活。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，也不会发生在像塑料或玻璃这样最常用于实验的刚性表面上。该提案中的实验将检查具有生理相关硬度的基质上的中性粒细胞功能，因为它们旨在模拟大多数组织中发现的弹性范围。

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.