Tuesday, July 1, 2025 7/1/2025

Usher Proteins in the Inner ear Structure and Function

Award Number: R01DC012564
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: 12/01/2012
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Usher Proteins in the Inner ear Structure and Function - Hearing loss (HL) is an etiologically diverse condition that can occur at any age and severity level, affecting 1 in 500 infants and more than 360 million people globally1; 2. In numerous ethnicities, we have previously identified pathogenic variants in the CIB2 gene encoding Calcium and Integrin-Binding protein 2 (CIB2) as the etiology of HL4-6. In past funding periods, we discovered that CIB2 is expressed in the mouse hair cell stereocilia and binds to the TMC1 and TMC2 components of the hair cell MET complex, and that deafness-causing CIB2 mutations disrupt these interactions. We concluded that CIB2 is essential for the MET function7. We also generated two mouse models carrying the human deafness-related Cib2 variants (Cib2F91S and Cib2R186W knock-ins) and characterized them together with a mouse line lacking CIB2 (Cib2ko). We found that Cib2F91S and Cib2ko mouse strains are deaf and lack typical MET responses in the auditory hair cells, despite the existence of tip links that are ordinarily responsible for gating the MET channels. In contrast, the p.R186W mutation does not disrupt the interaction between CIB2 and TMC1/27, and MET currents in mutant mice are diminished but still detectable. It is particularly intriguing that CIB2's participation in the MET machinery may be responsible for at least some of the several well-known effects of Ca2+ on hair cell mechanotransduction. Here, we will investigate the precise function of CIB2 in MET. We hypothesize that CIB2 is a calcium-dependent element that regulates sensitivity of the MET channels and force transmission to these channels in the mammalian auditory hair cells of. Our findings further determined that CIB2 deficiency causes an overgrowth of transducing shorter row stereocilia in the hair bundle without altering the non-transducing tallest row stereocilia7. This observation cannot be explained solely by the loss of mechanotransduction, since blockage of the MET channels causes an opposite effect, the retraction of transducing stereocilia8; 9. Hence, CIB2 must have some role in stereocilia growth, unrelated to mechanotransduction. Here, we will investigate the involvement of CIB2 in the molecular networks implicated in the development and patterning of auditory stereocilia bundles. A recent work has demonstrated functional redundancy between CIB2 and CIB3 proteins in regulating MET function3. Therefore, using in vitro and in vivo rescue experiments, we will test the hypothesis that cochlear hair cells require CIB2 for faster mechanotransduction and specific hair bundle shape. Finally, we will explore the function of CIB3 in hearing. The expected outcomes of this study are to uncover the precise mechanism of deafness associated with CIB2 deficiency, the physiological role of CIB proteins in hair cell functions, especially in MET, and their role in stereocilia staircase patterning. The potential for positive impact is inherent; deciphering the functions of HL proteins is a critical step towards the development of actual therapies for the treatment and/or prevention of HL.


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 = $632,866 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	000	13	11/8/2024	NON-COMPETING CONTINUATION	$569,580
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	001	13	4/29/2025	NON-COMPETING CONTINUATION	$63,286
														Subtotal = $632,866

Issue Date FY: 2024 ( Subtotal = $655,160 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	000	12	1/11/2024	COMPETING CONTINUATION	$655,160
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	002	12	7/30/2024	COMPETING CONTINUATION	$91,936
2024	2022	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	001	11	7/30/2024	NON-COMPETING CONTINUATION	-$91,936
														Subtotal = $655,160

Issue Date FY: 2022 ( Subtotal = $604,044 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	000	11	11/19/2021	NON-COMPETING CONTINUATION	$543,639
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	001	11	4/21/2022	NON-COMPETING CONTINUATION	$60,405
														Subtotal = $604,044

Issue Date FY: 2021 ( Subtotal = $616,389 )
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	000	10	11/13/2020	NON-COMPETING CONTINUATION	$554,749
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	001	10	1/7/2021	NON-COMPETING CONTINUATION	$61,640
														Subtotal = $616,389

Issue Date FY: 2020 ( Subtotal = $628,406 )
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	001	9	1/17/2020	NON-COMPETING CONTINUATION	$62,842
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	000	9	11/8/2019	NON-COMPETING CONTINUATION	$565,564
														Subtotal = $628,406

Issue Date FY: 2019 ( Subtotal = $640,027 )
2019	2019	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	000	8	11/23/2018	NON-COMPETING CONTINUATION	$640,027
														Subtotal = $640,027

Issue Date FY: 2018 ( Subtotal = $659,594 )
2018	2018	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	000	7	11/6/2017	COMPETING CONTINUATION	$659,594
2018	2017	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	001	6	4/4/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $659,594

Issue Date FY: 2017 ( Subtotal = $378,082 )
2017	2017	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	000	6	11/4/2016	NON-COMPETING CONTINUATION	$340,273
2017	2017	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	001	6	5/24/2017	NON-COMPETING CONTINUATION	$37,809
														Subtotal = $378,082

Issue Date FY: 2016 ( Subtotal = $378,237 )
2016	2016	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	001	5	1/8/2016	NON-COMPETING CONTINUATION	$37,825
2016	2016	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	000	5	11/2/2015	NON-COMPETING CONTINUATION	$340,412
														Subtotal = $378,237

Issue Date FY: 2015 ( Subtotal = $374,374 )
2015	2015	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	007	4	12/8/2014	NON-COMPETING CONTINUATION	-$340,340
2015	2015	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	009	4	1/13/2015	NON-COMPETING CONTINUATION	$34,034
2015	2015	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	002	4	11/13/2014	NON-COMPETING CONTINUATION	$340,340
2015	2015	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	008	4	12/9/2014	NON-COMPETING CONTINUATION	$340,340
2015	2014	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	004	3	12/4/2014	SUPPLEMENT FOR EXPANSION	-$70,000
2015	2014	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	005	3	12/4/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$181,382
2015	2014	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	006	3	12/5/2014	SUPPLEMENT FOR EXPANSION	$70,000
2015	2014	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	003	3	12/2/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$181,382
2015	2014	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Research Related to Deafness and Communication Disorders	001	3	10/22/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$62,285
2015	2014	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Research Related to Deafness and Communication Disorders	000	2	10/22/2014	NON-COMPETING CONTINUATION	$62,285
														Subtotal = $374,374

Issue Date FY: 2014 ( Subtotal = $449,112 )
2014	2014	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Research Related to Deafness and Communication Disorders	004	3	9/2/2014	SUPPLEMENT FOR EXPANSION	$70,000
2014	2014	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Research Related to Deafness and Communication Disorders	001	2	2/10/2014	NON-COMPETING CONTINUATION	$37,911
2014	2014	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Research Related to Deafness and Communication Disorders	000	2	11/8/2013	NON-COMPETING CONTINUATION	$341,201
2014	2014	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Research Related to Deafness and Communication Disorders	002	3	8/27/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$243,667
2014	2014	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Research Related to Deafness and Communication Disorders	003	2	8/27/2014	NON-COMPETING CONTINUATION	-$243,667
														Subtotal = $449,112

Issue Date FY: 2013 ( Subtotal = $380,523 )
2013	2013	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Research Related to Deafness and Communication Disorders	000	1	10/23/2012	NEW	$380,523
														Subtotal = $380,523

Grand Total All Awards = $6,396,814

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Usher Proteins in the Inner ear Structure and Function

Award Number: R01DC012564

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: 12/01/2012

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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