Hair dells are the receptors that vertebrates us to detect sound, head movement, vibrations, and gravity. Each of these sensations begins with a mechanical stimulus. Hair cells respond to this stimulus via a complex cellular process that shapes the primary afferent signal to the central nervous system. The first step in this process and the one on which all others depend is deflect of the hair cell's ciliary bundle. Unfortunately, the mechanical and cellular mechanisms that govern this first critical step are poorly understood. The long term goal of the proposed research is to understand these fundamental mechanisms of mechanotransduction by hair cells and to develop a realistic computational model of this process. It is a collaborative bioengineering effort that uses state-of-the-art imaging and computational technology. The proposed research has three bioengineering effort that uses state-of-the-art imaging and computational technology. The proposed research has three Specific Aims. (1) We will use light and electron microscopic techniques to characterize quantitatively the structure of hair cells, emphasizing those features of their ciliary bundles that are likely to affect the hair ells' mechanical performance, and we will use brightfield and confocal microscopy to visualize the coupling between hair bundles and the overlying otolithic membranes in living utricles. (2) We will incorporate these data into a structurally accurate finite element model of the ciliary bundle that will quantify the contribution of different structural elements (e.g., number, height, and interconnections of stereocilia) and the in vivo stimulus to the static stiffness and response dynamics of morphologically distinct varieties of hair cells. Then we will test and refine our model predictions by experimental tests on living bundles. (3) We will use our computational model to predict current-displacement relations in bundles of different types. Then we will use whole-cell patch clamp recording from living hair cells to further test and refine our model predictions. These studies will provide, important information about mechanisms of mechanotransduction and the functional significance of ciliary bundle structure. The resulting computational model will be a powerful resource in future attempts to understand the mechanical performance of any vertebrate hair cells.
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