Thursday, November 21, 2024 11/21/2024

Cochlear synaptopathy in noise-induced and age-related hearing loss: mechanisms and treatments

Award Number: R01DC000188
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary - Abstract The cochlear synapses of auditory nerve fibers (ANFs) degenerate before the sensory cells in both noise- induced and age-related hearing loss, leaving may inner hair cells (IHCs) partially disconnected from the brain. Although this synaptopathy has minimal effects on threshold sensitivity, it compromises hearing performance on complex auditory tasks and may be a major risk factor for tinnitus and hyperacusis. We have shown, in mouse, that augmenting cochlear levels of neurotrophin-3 (NT3) by local delivery, or by transgenic or virally driven overexpression, can rescue IHC synapses after noise and prevent their loss in the aging ear. We have also shown that post-noise IHC synapse regeneration occurs spontaneously in guinea pig, but not the mouse. Here, we combine the resources of the Liberman and Corfas laboratories to apply a range of ultrastructural, neurophysiological and molecular techniques to further probe the mechanisms and dynamics of synaptopathy, characterize its functional effects, validate the minimally invasive tests used to assess it in humans, probe the role of NT3 signaling as the key determinant of synaptopathy, and further refine translational approaches to reverse and/or prevent synaptopathy after noise or in aging. Specifically, in Aim 1, we use FIB-SEM and machine learning to automate serial-section ultrastructural analysis of the post-exposure damage and recovery of the IHC afferent innervation in mature mice vs. guinea pigs, to shed light on the reasons for the profound differences in regenerative capacity in the two species. In Aim 2, we combine population studies of single ANFs with intracellular labeling in synaptopathic guinea pigs at various stages of post-exposure recovery to a) characterize the extent to which the recovered synaptic counts reflect recovered function and b) to understand the contributions of different fiber populations to the non- invasive metrics of ANF function used in human studies of synaptopathy. In Aim 3, we test the hypothesized pivotal role of NT3 in the development and rescue of age- and noise-induced synaptopathy by a) determining if NT3 expression levels are upregulated by noise in guinea pigs but not in mice, and b) if drug-mediated blockade of cochlear NT3 receptors prevents the spontaneous post-exposure recovery of synapses in guinea pig. In Aim 4, we continue our refinement of gene-therapy approaches to the treatment of synaptopathy using an IHC-specific promoter in an AAV viral capsid to drive prolonged NT3 overexpression a) after noise and b) in an aging mouse model. Together these Aims will deepen our understanding of, and treatments for, this major contributor to the impairments of sensorineural hearing loss.


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: 2024 ( Subtotal = $690,222 )
2024	2024	MASSACHUSETTS EYE AND EAR INFIRMARY	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	002	43	2/21/2024	NON-COMPETING CONTINUATION	$621,200
2024	2024	MASSACHUSETTS EYE AND EAR INFIRMARY	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	003	43	5/2/2024	NON-COMPETING CONTINUATION	$69,022
2024	2023	MASSACHUSETTS EYE AND EAR INFIRMARY	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	001	42	11/21/2023	COMPETING CONTINUATION	$58,506
2024	2022	MASSACHUSETTS EYE AND EAR INFIRMARY	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	41	11/21/2023	NON-COMPETING CONTINUATION	-$58,506
														Subtotal = $690,222

Issue Date FY: 2023 ( Subtotal = $716,132 )
2023	2023	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	42	3/8/2023	COMPETING CONTINUATION	$716,132
														Subtotal = $716,132

Issue Date FY: 2022 ( Subtotal = $632,404 )
2022	2022	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	001	41	4/20/2022	NON-COMPETING CONTINUATION	$63,241
2022	2022	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	41	2/4/2022	NON-COMPETING CONTINUATION	$569,163
2022	2018	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	003	37	6/27/2022	COMPETING CONTINUATION	$596
2022	2017	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	002	36	6/27/2022	NON-COMPETING CONTINUATION	-$596
														Subtotal = $632,404

Issue Date FY: 2021 ( Subtotal = $632,404 )
2021	2021	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	40	2/22/2021	NON-COMPETING CONTINUATION	$632,404
														Subtotal = $632,404

Issue Date FY: 2020 ( Subtotal = $632,403 )
2020	2020	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	39	1/31/2020	NON-COMPETING CONTINUATION	$632,403
														Subtotal = $632,403

Issue Date FY: 2019 ( Subtotal = $632,403 )
2019	2019	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	38	1/11/2019	NON-COMPETING CONTINUATION	$632,403
														Subtotal = $632,403

Issue Date FY: 2018 ( Subtotal = $649,635 )
2018	2018	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	37	2/16/2018	COMPETING CONTINUATION	$649,635
2018	2017	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	001	36	7/26/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $649,635

Issue Date FY: 2017 ( Subtotal = $651,334 )
2017	2017	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	36	2/10/2017	NON-COMPETING CONTINUATION	$586,201
2017	2017	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	001	36	5/24/2017	NON-COMPETING CONTINUATION	$65,133
														Subtotal = $651,334

Issue Date FY: 2016 ( Subtotal = $651,334 )
2016	2016	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	35	1/14/2016	EXTENSION WITH OR WITHOUT FUNDS	$651,334
														Subtotal = $651,334

Issue Date FY: 2015 ( Subtotal = $644,822 )
2015	2015	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	34	2/28/2015	NON-COMPETING CONTINUATION	$644,822
														Subtotal = $644,822

Issue Date FY: 2014 ( Subtotal = $729,221 )
2014	2014	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	33	2/7/2014	NON-COMPETING CONTINUATION	$729,221
														Subtotal = $729,221

Issue Date FY: 2013 ( Subtotal = $761,387 )
2013	2013	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	003	32	2/26/2013	SUPPLEMENT FOR EXPANSION	$84,967
2013	2013	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	002	32	2/4/2013	COMPETING CONTINUATION	$0
2013	2013	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	001	32	1/31/2013	COMPETING CONTINUATION	$669,370
2013	2013	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	31	1/1/2013	SUPPLEMENT FOR EXPANSION	$7,050
														Subtotal = $761,387

Issue Date FY: 2012 ( Subtotal = $515,671 )
2012	2012	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	31	2/14/2012	NON-COMPETING CONTINUATION	$515,671
														Subtotal = $515,671

Issue Date FY: 2011 ( Subtotal = $515,671 )
2011	2011	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	001	30	6/2/2011	NON-COMPETING CONTINUATION	$32,772
2011	2011	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	30	2/11/2011	NON-COMPETING CONTINUATION	$482,899
														Subtotal = $515,671

Issue Date FY: 2010 ( Subtotal = $520,929 )
2010	2010	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	29	2/5/2010	NON-COMPETING CONTINUATION	$520,929
														Subtotal = $520,929

Issue Date FY: 2009 ( Subtotal = $510,866 )
2009	2009	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	001	28	3/18/2009	NON-COMPETING CONTINUATION	$51,086
2009	2009	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	28	1/28/2009	NON-COMPETING CONTINUATION	$459,780
														Subtotal = $510,866

Issue Date FY: 2008 ( Subtotal = $465,590 )
2008	2008	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	27	2/19/2008	COMPETING CONTINUATION	$465,590
														Subtotal = $465,590

Issue Date FY: 2007 ( Subtotal = $451,001 )
2007	2007	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	26	2/23/2007	NON-COMPETING CONTINUATION	$451,001
														Subtotal = $451,001

Issue Date FY: 2006 ( Subtotal = $453,722 ) (Continued on the next page)
Grand Total All Awards = $14,441,467

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Cochlear synaptopathy in noise-induced and age-related hearing loss: mechanisms and treatments

Award Number: R01DC000188

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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