Neutrophil Mechanosensing

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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.