verbatim) Acute narrowing of the airway lumen in asthma is driven by myosin motors that exert their mechanical effects within a cytoskeletal scaffolding that is both deformable and in a continuous state of remodeling. The mechanical properties of that scaffolding are not well defined. This BRP application describes a multi-disciplinary design-directed bioengineering project to fill that gap of knowledge. We propose to develop a micromechanical technology to measure the rheological properties of adherent living airway smooth muscle cells in culture, and the time-course of mechanical changes that occur in response to contractile stimuli or after genetic manipulation of cytoskeletal proteins. Ligand-coated ferromagnetic microbeads are bound to the cytoskeleton, and oscillatory mechanical torques are then applied to the bead by a sinusoidally-varying external magnetic field. Resulting oscillatory bead motions deform the cell, and can be determined by measuring changes of the remanent magnetic field due to bead rotations or, alternatively, by direct observation of oscillatory bead displacements using light microscopy; these are complementary detection methods each with special advantages. This technology becomes, in effect, a micro-rheometry system that can probe - in cell culture conditions - contractile responses and underlying cellular rate processes over time scales as short as tens of milliseconds to as long as hundreds of seconds. Thus, it measures mechanical properties of cells using deformation times (and stress magnitudes) that span the physiological range. We propose to develop this technology and then use it to test the hypothesis that the contractile response of human airway smooth muscle cells in culture is attenuated by overexpression of heat shock protein 27 (HSP27) dominant negative mutants. This hypothesis bears upon a question whose importance has been identified only recently, namely, the stability of the cytoskeleton of the airway smooth muscle cell and the role of CSK stability in airway narrowing in asthma. This BRP is led by Harvard University with Dalhousie University and the University of Barcelona as participating institutions.
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