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High-probability grants
According to our matching algorithm, Robert Fettiplace is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
1992 — 2021 |
Fettiplace, Robert |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Intracellular Calcium in Hair Cells @ University of Wisconsin-Madison
DESCRIPTION (provided by applicant): 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.
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2016 — 2020 |
Fettiplace, Robert |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Development of Mechanotransduction in Cochlear Hair Cells @ University of Wisconsin-Madison
PROJECT SUMMARY The long-term objective is to understand the operation and structure of the mechanotransducer (MT) channel in auditory hair cells. Present evidence about this channel, unlike other ion channels, is very incomplete, and both the molecular identity of the pore-forming subunit and the mechanism of channel gating are controversial. Effects on transduction occur with mutations in TMC1 or LHFPL5 which can interact with the tip link constituent PCDH15. The MT channel is thought to be located at the lower end of the tip link and to be activated by deflections of the hair bundle towards its taller edge, thus tensioning the tip links. However, under some circumstances, including destruction of the tip links, an MT current can also be activated by bundle displacements of opposite polarity. We have preliminary evidence that such `reverse-polarity' MT currents are also prominent during hair bundle development, when they precede the appearance of the normal MT channels. The goal of the project is to investigate these anomalous developmental channels in the hope that it will enlighten how the normal MT channel is transported to its final location, and what trafficking proteins are needed. MT currents will be recorded during mechanical stimulation of hair cells in isolated cochleas of perinatal wild-type and mutant mice. Specific aims are: (1) to document the time of emergence of the reverse- polarity current and its relation to the normal MT current during the days around birth; (2) to compare properties of the reverse-polarity channels with the normal ones and to determine their location in the hair bundle or plasma membrane using fast confocal imaging of Ca2+ influx through these channels; (3) to ascertain whether reverse-polarity channels observed developmentally are susceptible to destruction of inter-ciliary links. Electron microscopy will be used to describe the different types and orientations of links and to describe bundle morphology during development to relate to the reverse-polarity current; (4) to investigate pathways for inserting reverse-polarity MT channels into the plasma membrane, testing the hypothesis that the channels are trafficked to the apical membrane and then translocated to the tips of the stereocilia to become mature MT channels; (5) to investigate the dependence of the reverse-polarity currents on mutations (including those in protocadherin-15, myosin VIIa, LHFPL5 and isoforms of TMC), in which the transduction machinery is perturbed. It is hoped that the results will provide evidence on the molecular composition of the hair cell transduction apparatus and its method of assembly.
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