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Probing how hair bundle mechanical properties shape the mechanotransducer receptor current

Award Number: R01DC021448
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/18/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Probing how hair bundle mechanical properties shape the mechanotransducer receptor current - Abstract: Auditory and vestibular sensory cells use the hair bundle, a stair-cased array of actin filled stereocilia, to translate mechanical motion into an electrical signal. Mechanically-gated (MET) ion channels located at the tips of shorter stereocilia are activated by force created by the pulling of a tip link that extends between stereocilia. As sensory hair bundles are a major site for both genetic disorders like Ushers syndrome and are also susceptible to damage from noise and aging, understanding how these bundles operate is critical to designing therapies for prevention and restoration of function. Mammalian cochlear hair bundles have unusual morphologies and interstereocilia connectivity that is not as tight as other inner ear end organs. There is considerable debate as to the mechanisms underlying processes impacting MET currents and hair bundle mechanics, like fast and slow adaptation, gating compliance and voltage driven responses. There is further controversy over whether we truly have causal links between MET current responses and mechanical, molecular mechanisms. Before being able to use the power of genetic manipulation of newly identified MET molecules, we need a clear understanding of hair bundle biophysical properties and how they impact MET receptor currents. We hypothesize that the lack of connectivity in bundle motion is to optimize the hair bundle's response to natural stimulation and that synchronization of stereocilia comes from the tectorial membrane (OHCs) or the fluid stimulation (IHCs). We further hypothesize that we will identify mechanical correlates for fast and slow adaptation as well as gating compliance; however, we do expect there to be less slow adaptation as compared to other hair cell types but also that the mechanism of slow adaptation will not align with classical theories. And finally. we hypothesize that MET channel properties work with hair bundle mechanics to create tuning of the receptor current. We will investigate each of these hypotheses in the following specific aims. SA1 will generate a comprehensive data set of MET channel and hair bundle properties at multiple frequency positions from rats and mice P10-12 of age. By taking advantage of three modes of stimulations, wide probe, fluid jet and the newly developed narrow probe, we can separate between MET channel and hair bundle properties. SA2 will directly address hair bundle mechanics and known hair bundle properties using the newly developed high-speed imaging with either narrow probe or fluid jet technology. Experiments will target MET channel gating compliance, fast and slow adaptation and voltage dependent mechanical hair bundle responses. SA3 will generate frequency response curves under physiological conditions using the wide probe and fluid jet to define the filtering properties of the channel and the hair bundle. Completion of these aims will provide an unprecedented level of quantitative information as to how the hair bundle moves and how this motion shapes the MET receptor current generated. They will be the standard by which molecular manipulations can be assessed.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $627,260 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Research Related to Deafness and Communication Disorders	000	4	9/1/2026	NON-COMPETING CONTINUATION	$627,260
														Subtotal = $627,260

Issue Date FY: 2025 ( Subtotal = $639,962 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Research Related to Deafness and Communication Disorders	000	3	8/14/2025	NON-COMPETING CONTINUATION	$639,962
														Subtotal = $639,962

Issue Date FY: 2024 ( Subtotal = $648,830 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Research Related to Deafness and Communication Disorders	001	2	8/13/2024	NON-COMPETING CONTINUATION	$652,287
2024	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Research Related to Deafness and Communication Disorders	000	1	10/12/2023	NEW	-$3,457
														Subtotal = $648,830

Issue Date FY: 2023 ( Subtotal = $667,704 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Research Related to Deafness and Communication Disorders	000	1	9/18/2023	NEW	$667,704
														Subtotal = $667,704

Grand Total All Awards = $2,583,756

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Probing how hair bundle mechanical properties shape the mechanotransducer receptor current

Award Number: R01DC021448

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/18/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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