Wednesday, December 11, 2024 12/11/2024

Molecular Mechanisms of Auditory Transduction

Award Number: R01DC000304
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 The most fundamental event in the initiation of hearing is the conversion of sound into an electrical signal by the opening of ion channels in hair cells. We know that TMC1 and TMC2 are the pore-forming subunits of the mechanotransduction complex, we know the general tertiary structure of TMCs, and we know which transmembrane domains constitute the pore. But we now need to know specifically how the sound-evoked increase in tip-link tension leads to channel opening: how does PCDH15 in the tip link attach to TMC1, what moves in TMC1 to open the pore, and how does tension propagate through the TMC channel to cause that opening? In this project we will first identify the parts of PCDH15 that bind to TMC1, using a combination of co- immunoprecipitation, biolayer interferometry, protein biochemistry, site-directed mutagenesis, and single-cell electrophysiology. Mutagenesis will be guided by cryo-electron microscopy of a related TMC channel and by new atomic structures generated by structure-prediction software such as AlphaFold2. We will then identify the parts of TMC1 that bind to PCDH15, using the same methods. In parallel, we will evaluate recent data from other laboratories on regions of LHFPL5 that bind to TMC1. To understand the gating of TMC1, we will use additional protein structure predictions from AlphaFold2 to identify different conformational states of TMC1 that may represent open and closed states of the channel. Combining knowledge of the binding interface and the predicted gating transitions, we can use molecular dynamics to determine whether and how the application of force—through either PCDH15 or LHFPL5—tends to produce channel opening. We will then test the models generated by molecular dynamics, by introducing cysteine residues at key locations in TMC and transiently linking them with heavy metal ions or bivalent MTS reagents. These bridges will lock TMC in one or another conformation. By expressing different cysteine mutants in hair cells and applying these reagents while recording transduction currents, we can determine whether open or closed states are favored, and thereby test the predicted gating movements. We will also test whether predicted movement of an intracellular loop drives the gating movement, by inserting flexible peptide sequences. This will generate an atomic-level understanding of mechanotransduction, unprecedented for hair cells or for any eukaryotic force-gated ion channel. It will also provide deep insight into the function of TMC1 and PCDH15, and how mutations in these proteins cause hereditary deafness.


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 = $607,707 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	37	11/19/2024	NON-COMPETING CONTINUATION	$607,707
														Subtotal = $607,707

Issue Date FY: 2024 ( Subtotal = $674,797 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	36	10/18/2023	COMPETING CONTINUATION	$674,797
														Subtotal = $674,797

Issue Date FY: 2021 ( Subtotal = -$23,011 )
2021	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	35	6/22/2021	NON-COMPETING CONTINUATION	-$23,011
														Subtotal = -$23,011

Issue Date FY: 2020 ( Subtotal = $418,634 )
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	35	1/17/2020	NON-COMPETING CONTINUATION	$418,634
														Subtotal = $418,634

Issue Date FY: 2019 ( Subtotal = $419,797 )
2019	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	34	2/7/2019	NON-COMPETING CONTINUATION	$419,797
														Subtotal = $419,797

Issue Date FY: 2018 ( Subtotal = $420,922 )
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	001	33	4/5/2018	NON-COMPETING CONTINUATION	$42,093
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	33	1/25/2018	NON-COMPETING CONTINUATION	$378,829
														Subtotal = $420,922

Issue Date FY: 2017 ( Subtotal = $422,016 )
2017	2017	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	001	32	5/24/2017	NON-COMPETING CONTINUATION	$42,203
2017	2017	HARVARD COLLEGE, PRESIDENT & FELLOWS OF	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	32	1/18/2017	NON-COMPETING CONTINUATION	$379,813
														Subtotal = $422,016

Issue Date FY: 2016 ( Subtotal = $437,573 )
2016	2016	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	31	2/5/2016	COMPETING CONTINUATION	$437,573
2016	2014	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	001	30	2/5/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $437,573

Issue Date FY: 2014 ( Subtotal = $348,662 )
2014	2014	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	30	5/28/2014	NON-COMPETING CONTINUATION	$348,662
														Subtotal = $348,662

Issue Date FY: 2013 ( Subtotal = $331,228 )
2013	2013	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	29	5/17/2013	NON-COMPETING CONTINUATION	$331,228
														Subtotal = $331,228

Issue Date FY: 2012 ( Subtotal = $348,662 )
2012	2012	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	28	5/16/2012	NON-COMPETING CONTINUATION	$348,662
														Subtotal = $348,662

Issue Date FY: 2011 ( Subtotal = $348,662 )
2011	2011	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	27	6/6/2011	NON-COMPETING CONTINUATION	$348,662
														Subtotal = $348,662

Issue Date FY: 2010 ( Subtotal = $360,188 )
2010	2010	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	26	6/1/2010	COMPETING CONTINUATION	$360,188
2010	2009	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	001	25	6/1/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $360,188

Issue Date FY: 2009 ( Subtotal = $348,980 )
2009	2009	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	25	3/19/2009	NON-COMPETING CONTINUATION	$348,980
														Subtotal = $348,980

Issue Date FY: 2008 ( Subtotal = $348,980 )
2008	2008	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	24	3/21/2008	NON-COMPETING CONTINUATION	$348,980
														Subtotal = $348,980

Issue Date FY: 2007 ( Subtotal = $353,577 )
2007	2007	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	23	3/12/2007	NON-COMPETING CONTINUATION	$353,577
														Subtotal = $353,577

Issue Date FY: 2006 ( Subtotal = $364,137 )
2006	2006	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	22	2/17/2006	NON-COMPETING CONTINUATION	$364,137
														Subtotal = $364,137

Issue Date FY: 2005 ( Subtotal = $372,900 )
2005	2005	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	21	2/7/2005	COMPETING CONTINUATION	$372,900
														Subtotal = $372,900

Issue Date FY: 2004 ( Subtotal = $319,328 )
2004	2004	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	20	3/5/2004	NON-COMPETING CONTINUATION	$319,328
														Subtotal = $319,328

Issue Date FY: 2003 ( Subtotal = $319,328 )
2003	2003	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	19		NON-COMPETING CONTINUATION	$319,328
														Subtotal = $319,328

Issue Date FY: 2002 ( Subtotal = $315,330 )
2002	2002	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	17	8/23/2002	NON-COMPETING CONTINUATION	$102,843
2002	2002	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Research Related to Deafness and Communication Disorders	000	18	8/23/2002	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$212,487
														Subtotal = $315,330

Issue Date FY: 2001 ( Subtotal = $319,208 )
2001	2001	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	16	3/22/2001	NON-COMPETING CONTINUATION	$319,208
														Subtotal = $319,208

Issue Date FY: 2000 ( Subtotal = $319,208 ) (Continued on the next page)
Grand Total All Awards = $9,005,527

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Molecular Mechanisms of Auditory Transduction

Award Number: R01DC000304

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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