Neutrophil Mechanosensing

描述（由申请人提供）：无论病因如何，神经元迁移是所有炎症反应的共同方面，其调节是本提案的主题。迁移依赖于由细胞产生并施加到下层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是必不可少的，因为力不足或过大将减缓或阻止移动性。牵引力的调节，特别是当它们与白细胞有关时，是复杂的并且知之甚少。组织内细胞的机械感测是指细胞感知其环境的机械特性差异的能力。环境的物理性质已被证明会影响基因表达，增殖，细胞骨架组织和许多细胞类型的生存。中性粒细胞的宿主防御功能相对较少发生在循环或非粘附细胞中，也不发生在塑料或玻璃等刚性表面上。在这个建议中的实验将检查中性粒细胞功能的基质是生理相关的刚度，因为它们的目的是模仿在大多数组织中发现的弹性范围。据推测，中性粒细胞解释的机械刚度的底层基板，并响应在迁移过程中的空间和时间的牵引力调节的变化。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是将机械和生化信号转化为细胞骨架改变，最终决定中性粒细胞的形状和功能。 炎症是对损伤或感染的基本反应，因为它可以防止感染蔓延并开始愈合过程。白色血细胞（白细胞）在血流中持续循环，但对局部损伤部位作出反应，它们必须离开血液并通过受损组织迁移以开始愈合。迁移依赖于由细胞产生并施加到下层细胞外基质上的牵引力。组织内细胞的机械感测是指细胞感知其环境的机械特性差异的能力。环境的物理性质已被证明会影响基因表达，增殖，细胞骨架组织和许多细胞类型的生存。中性粒细胞的宿主防御功能相对较少，发生在循环或非粘附细胞中，也不发生在塑料或玻璃等刚性表面上，这些表面是最常用于实验的表面。在这个建议中的实验将检查中性粒细胞功能的基质是生理相关的刚度，因为它们的目的是模仿在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.