Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Molecular roles in active and passive mechanics in cochlear hair bundles

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Sound vibrations enter the outer ear through the ear canal and are converted into pressure waves by the middle ear. Pressure waves in the inner ear are converted to an electrical signal via the mechano-electrical transduction (MET) process in the hair bundle of sensory hair cells; this electrical signal drives synaptic transmission resultin in information traveling to the brain. Failures in this process lead to hearing loss and deafness. Multiple human genetic mutations exhibit deficits in the MET process. Understanding the basic properties of MET will lead to a better understanding of genetic deafness, leading to targeted treatments and therapies. A growing body of data on mammalian cochlear hair cell MET properties is incompatible with existing molecular models of MET. Specifically, adaptation, a key process of MET universally accepted to be signaled by calcium, does not appear to be driven by calcium ion entry, thus challenging current models of adaptation. To better understand the underlying mechanisms responsible for cochlear MET, mechanical changes in the hair bundle need to be measured at rates that match the fast rates of MET processes in cochlear hair cells. In this proposal, to overcome current technological limitations, new micro-electro-mechanical systems (MEMS) devices are developed to specifically measure cochlear hair bundle mechanics. Using whole-cell voltage clamp recordings of mammalian cochlear hair cells along with new MEMS devices, kinetics and mechanics of fast cochlear MET processes will be measured. This data will be used to generate new models of cochlear MET. Myosin motors localized to the upper tip-link region have been proposed to be important to MET. New experiments in the cochlea will be performed using these novel MEMS devices to characterize mechanics of the hair bundle when modifying motor activity. From these experiments, the role of molecular motors as well as the upper tip-link region in cochlear hair cells in MET processes will be determined. During acoustic trauma, hair bundles are stressed from overstimulation resulting in stiffness changes to the hair bundle. To characterize mechanical properties of the mammalian hair bundle, this proposal aims to quantify the contribution of stereocilia links and the stereocila rootlet to passive hair bundle stiffness using drug application and genetic mouse models lacking specific structures. The experiments in this proposal will further our understanding of the molecular mechanisms of mammalian cochlear MET. Understanding the crucial components in passive hair bundle stiffness will lay groundwork for understanding the key regulation points of hair bundle properties and the effects of acoustic trauma on stereocilia. The technology developed will greatly enhance auditory research and likely have broader mechanics applications in the auditory field and beyond.
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