The long-term objectives are to understand the cellular mechanisms of transduction in auditory hair cells and delineate the factors underlying the cochlea's tonotopic organization. Experiments will focus on transducer channel adaptation and hair bundle mechanics to define their regulation by Ca2+ and roles in frequency selectivity. A prime objective is to improve the speed of the mechanical stimulator and utilize different preparations and conditions to obtain accurate measures of the kinetics of transduction and active bundle motion. Hair cell responses will be measured in the isolated cochleae of both mammals and birds and will be combined with intracellular Ca2+ imaging.
Specific aims are: (1) to record mechanotransducer currents in gerbil and rat hair cells before and after the onset of hearing, documenting the changes in kinetics and other properties with cochlear location;(2) to characterize single mechanotransducer channels and investigate their variation with cochlear location and modulation by Ca2+ and cyclic AMP, to provide a baseline for candidate channel proteins;(3) to measure the mechanical properties of hair bundles and search for spontaneous and active bundle motion in mammalian hair cells. The interaction between active bundle motion and outer hair cell contractility will be used to assess the roles of the two processes in amplification and frequency tuning in the intact mammalian cochlea. (4) to record mechanotransducer currents and measure hair bundle mechanics of short (outer) hair cells in the chick auditory papilla as a likely but unproven site where active hair bundle motion is used to augment frequency selectivity. Comparison with the properties of the mammalian hair bundles will provide insight into the evolution of cochlear amplification;(5) to measure and alter the concentration of Ca2+ in hair bundles and relate it to control of mechanotransducer channel adaptation and active hair bundle motion. The contributions of Ca2+ buffering and uptake into intracellular compartments, especially the mitochondria, to limit Ca2+ transients will be studied. Since hair cells experience large Ca2+ loads, disturbance of Ca2+ homeostasis may be a leading cause of injury. Ca2+ modulation of mechanotransducer channels is probably common to all hair cells and may be the site of irreversible damage during noise exposure, poisoning with ototoxic agents or aging. Loss of hearing with aging or over-stimulation is often restricted to high frequencies and is linked to degeneration of hair cells at one end of the cochlea. The work will address the reasons for this differential sensitivity by mapping the properties of transduction with location in the mammalian cochlea. It is hypothesized that the majority of Ca2+ enters the hair cells through the MT channels and the increased vulnerability of high frequency outer hair cells reflects a greater Ca2+ influx because of larger MT currents. Hearing impairment is the most common disabling sensory defect in humans. Severe to profound hearing loss, largely attributable to injury to the sensory hair cells, affects 1 in 1,000 newborns, and 60% of people older than 70 years have a hearing deficit of at least 25 dB. It has a range of causes, including genetic, noise or drug induced, as well as being age-related but the basic mechanisms of damage and cell death in most cases are not well understood. The work will address the mechanisms by documenting the mechanical and electrical properties of auditory hair cells and their modulation by calcium ions. We hypothesize that calcium overloading leading to mitochondrial dysfunction is a major route to cell damage.
Hearing impairment is the most common disabling sensory defect in humans. Severe to profound hearing loss, largely attributable to injury to the sensory hair cells, affects 1 in 1,000 newborns, and 60% of people older than 70 years have a hearing deficit of at least 25 dB. It has a range of causes, including genetic, noise or drug induced, as well as being age-related but the basic mechanisms of damage and cell death in most cases are not well understood. The work will address the mechanisms by documenting the mechanical and electrical properties of auditory hair cells and their modulation by calcium ions. We hypothesize that calcium overloading leading to mitochondrial dysfunction is a major route to cell damage.
|Beurg, Maryline; Cui, Runjia; Goldring, Adam C et al. (2018) Variable number of TMC1-dependent mechanotransducer channels underlie tonotopic conductance gradients in the cochlea. Nat Commun 9:2185|
|Wu, Zizhen; Grillet, Nicolas; Zhao, Bo et al. (2017) Mechanosensory hair cells express two molecularly distinct mechanotransduction channels. Nat Neurosci 20:24-33|
|Giese, Arnaud P J; Tang, Yi-Quan; Sinha, Ghanshyam P et al. (2017) CIB2 interacts with TMC1 and TMC2 and is essential for mechanotransduction in auditory hair cells. Nat Commun 8:43|
|Fettiplace, Robert (2017) Hair Cell Transduction, Tuning, and Synaptic Transmission in the Mammalian Cochlea. Compr Physiol 7:1197-1227|
|Beurg, Maryline; Fettiplace, Robert (2017) PIEZO2 as the anomalous mechanotransducer channel in auditory hair cells. J Physiol 595:7039-7048|
|Beurg, Maryline; Goldring, Adam C; Ricci, Anthony J et al. (2016) Development and localization of reverse-polarity mechanotransducer channels in cochlear hair cells. Proc Natl Acad Sci U S A 113:6767-72|
|Fettiplace, Robert (2016) Is TMC1 the Hair Cell Mechanotransducer Channel? Biophys J 111:3-9|
|Beurg, Maryline; Goldring, Adam C; Fettiplace, Robert (2015) The effects of Tmc1 Beethoven mutation on mechanotransducer channel function in cochlear hair cells. J Gen Physiol 146:233-43|
|Beurg, Maryline; Xiong, Wei; Zhao, Bo et al. (2015) Subunit determination of the conductance of hair-cell mechanotransducer channels. Proc Natl Acad Sci U S A 112:1589-94|
|Beurg, Maryline; Kim, Kyunghee X; Fettiplace, Robert (2014) Conductance and block of hair-cell mechanotransducer channels in transmembrane channel-like protein mutants. J Gen Physiol 144:55-69|
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