Thursday, September 18, 2025 9/18/2025

Investigating the mechanisms of stereocilia length regulation and innovative strategies for restoring hearing

Award Number: R01DC021075
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: 04/10/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Investigating the mechanisms of stereocilia length regulation and innovative strategies for restoring hearing - Abstract Sensorineural hearing loss is a debilitating condition with no cure that directly impacts >30 million people. A common cause of inherited hearing loss is the disruption of cochlear hair cell stereocilia, which are essential for transducing sound vibrations to the brain. For proper function, stereocilia must be tall enough to reach the tectorial membrane (TM) and form stereocilia-TM junctions (STJs). Stereocilia elongation greatly depends on actin regulation; as such, disruption of actin regulatory proteins and other cytoskeletal elements cause profound hearing loss in humans and model organisms. Thus, it is critical to elucidate the dynamic regulation of stereocilia lengths to understand normal hearing and determine how to rescue stereocilia-related hearing loss. Previous work demonstrated that stereocilia actin filament elongation depends on epidermal growth factor pathway substrate 8 (Eps8), an actin-regulatory protein that is critical for hearing in both mice and humans. Eps8 paradoxically contains domains with both actin filament capping and bundling activities, which are typically associated with shortening or elongation of actin filaments, respectively. Moreover, it was found that two other deafness-associated proteins essential for stereocilia elongation, Myosin-XVa (MyoXVa) and whirlin, bind to Eps8 at stereocilia tips in a tripartite complex. Preliminary data show that stereocilin, another deafness-associated protein which links stereocilia to the TM at STJs, is not properly targeted to stereocilia tips in Eps8, MyoXVa, or whirlin knockout (KO) mice, and that all these mice lack normal STJs. Moreover, early (≤postnatal day 1) adeno-associated virus (AAV)-mediated delivery of Eps8 can rescue stereocilia elongation, stereocilin localization, and STJs in Eps8 KO mouse apical hair cells, suggesting that it may be possible to rescue hearing function. This proposal tests the hypothesis that Eps8 regulates stereocilia elongation and the proper formation of STJs by directly regulating actin bundle growth through its C-terminal actin capping and bundling regions and indirectly regulating stereocilia growth through interactions with MyoXVa and whirlin. Further, it is proposed that there is a critical window of hair cell maturation during which stereocilia plasticity is sufficient for full rescue. To test these hypotheses, an AAV-mediated delivery of Eps8 mutants lacking either or both capping and bundling domains (Aim 1) or Eps8 mutants lacking MyoXVa-, whirlin-, or actin-binding activity (Aim 2) in Eps8 KO models will be used. In addition, novel light- and chemically-inducible Eps8 mice will be employed to explore cochlear plasticity and define the critical window for restoring hair cell function in vivo (Aim 3A). The potential for partial reprogramming to expand or restore the critical window for rescuing hair cell function (Aim 3B) will be investigated. Thus, by combining advanced genetic tools, high-resolution imaging, and hearing assays, the basic cell biological mechanisms of stereocilia length regulation will be elucidated and innovative strategies for restoring hearing will be developed.


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: 2025 ( Subtotal = $895,009 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Research Related to Deafness and Communication Disorders	003	4	7/9/2025	NON-COMPETING CONTINUATION	$747,995
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Research Related to Deafness and Communication Disorders	000	3	11/27/2024	SUPPLEMENT FOR EXPANSION	$73,507
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Research Related to Deafness and Communication Disorders	004	4	7/15/2025	SUPPLEMENT FOR EXPANSION	$73,507
2025	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Research Related to Deafness and Communication Disorders	002	3	7/1/2025	NON-COMPETING CONTINUATION	$0
2025	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Research Related to Deafness and Communication Disorders	001	3	5/22/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $895,009

Issue Date FY: 2024 ( Subtotal = $652,074 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Research Related to Deafness and Communication Disorders	002	3	4/18/2024	NON-COMPETING CONTINUATION	$752,239
2024	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Research Related to Deafness and Communication Disorders	000	1	12/10/2023	NEW	-$551,006
2024	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Research Related to Deafness and Communication Disorders	003	1	6/24/2024	NEW	-$8,993
2024	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Research Related to Deafness and Communication Disorders	004	2	6/24/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$8,993
2024	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Research Related to Deafness and Communication Disorders	001	2	12/11/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$450,841
														Subtotal = $652,074

Issue Date FY: 2023 ( Subtotal = $918,882 )
2023	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Research Related to Deafness and Communication Disorders	000	1	4/10/2023	NEW	$918,882
														Subtotal = $918,882

Grand Total All Awards = $2,465,965

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Investigating the mechanisms of stereocilia length regulation and innovative strategies for restoring hearing

Award Number: R01DC021075

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: 04/10/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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