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Genetic dissection of auditory circuit assembly

Award Number: R01DC009223
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: 05/15/2009
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Genetic dissection of auditory circuit assembly - Project Summary Spiral ganglion neurons (SGNs) encode everything an animal hears and send this information to the brain. In order to achieve rapid and reliable signal transmission, SGNs exhibit a number of specialized properties, including the ability to respond to glutamate via large, AMPA-receptor rich post-synaptic densities. Although all SGNs are glutamatergic, differences in the nature of their synapses and their responses to sound indicate that there are three distinct subtypes. High spontaneous firing rate (SR) SGNs have low thresholds and are likely the first to respond to sound. Low SR SGNs have higher thresholds and are proposed to improve the ability to detect sounds in noise; medium SR SGNs fall in between. These physiological differences are accompanied by parallel changes in the abundance of AMPA receptors and the size of the opposing pre-synaptic ribbon. Low SR SGN synapses are more vulnerable to the effects of noise exposure, which may be why some people have trouble understanding what they hear despite normal auditory thresholds. The long term goal of this project is to understand how SGNs acquire the properties needed for the perception of sound. More immediately, we will define the intrinsic transcriptional networks that endow SGN subtypes with their distinct properties and functions. We hypothesize that SGN diversification depends on the combined activities of a pan-SGN Gata3 network and a subtype-specific program driven by the transcription factor Runx1. Previously, we showed that Gata3 influences multiple features of SGN differentiation, acting in part through the transcription factor Mafb (Lu et al., 2011; Appler et al., 2013; Yu et al., 2013). In Mafb mutant mice, SGNs do not develop normal post-synaptic densities. Subsequently, we showed that Type I SGNs fall into three molecular distinct subtypes (Ia, Ib, and Ic) that match the features of high, medium, and low SR SGNs respectively (Shrestha et al., 2018). New preliminary studies suggest that diversification among Type I SGNs requires the transcription factor Runx1, which is restricted to Ib and Ic subtypes by late embryogenesis and then maintained throughout life. Further, Ic SGNs appear to be lost from Runx1 conditional knock-out (CKO) mice, as indicated by changes in gene expression and altered ABR responses. Here, we will define the role of Runx1 and its relationship with Gata3. We will perform a thorough analysis of Runx1CKO mice, examining SGN composition, synaptic heterogeneity, and the effects on hearing. In parallel, we will use genetic and viral overexpression approaches to learn how Gata3 and its Maf effectors influence the emergence of subtype identity and synaptic heterogeneity in vivo. Using single cell and bulk RNA-sequencing, we will define the molecular programs active in developing Ib/c SGNs and test how these programs are altered by loss of Runx1 or Gata3, as well as how the Maf factors contribute. These studies will elucidate the molecular programs driving SGN diversification, show how this diversity influences hearing, and may reveal a way to replace lost Ic SGNs and hence restore normal hearing after acoustic trauma.


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 = $0 )
2026	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	15	11/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $606,723 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	001	16	4/1/2025	COMPETING CONTINUATION	$606,723
2025	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	15	4/1/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $606,723

Issue Date FY: 2024 ( Subtotal = $569,543 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	15	3/27/2024	NON-COMPETING CONTINUATION	$569,543
2024	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	001	14	5/14/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $569,543

Issue Date FY: 2023 ( Subtotal = $662,696 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	001	14	9/8/2023	SUPPLEMENT FOR EXPANSION	$93,153
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	14	3/15/2023	NON-COMPETING CONTINUATION	$569,543
														Subtotal = $662,696

Issue Date FY: 2022 ( Subtotal = $569,543 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	13	4/22/2022	NON-COMPETING CONTINUATION	$569,543
														Subtotal = $569,543

Issue Date FY: 2021 ( Subtotal = $575,898 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	12	3/17/2021	NON-COMPETING CONTINUATION	$575,898
2021	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	002	11	3/19/2021	COMPETING CONTINUATION	$1
2021	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	001	10	3/19/2021	NON-COMPETING CONTINUATION	-$1
														Subtotal = $575,898

Issue Date FY: 2020 ( Subtotal = $575,898 )
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	11	3/19/2020	COMPETING CONTINUATION	$575,898
														Subtotal = $575,898

Issue Date FY: 2019 ( Subtotal = $524,603 )
2019	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	10	3/18/2019	NON-COMPETING CONTINUATION	$524,603
														Subtotal = $524,603

Issue Date FY: 2018 ( Subtotal = $522,714 )
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	001	9	4/6/2018	NON-COMPETING CONTINUATION	$52,271
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	9	3/29/2018	NON-COMPETING CONTINUATION	$470,443
														Subtotal = $522,714

Issue Date FY: 2017 ( Subtotal = $509,509 )
2017	2017	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	001	8	5/24/2017	NON-COMPETING CONTINUATION	$51,297
2017	2017	HARVARD COLLEGE, PRESIDENT & FELLOWS OF	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	8	3/17/2017	NON-COMPETING CONTINUATION	$458,212
														Subtotal = $509,509

Issue Date FY: 2016 ( Subtotal = $511,230 )
2016	2016	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	7	3/18/2016	NON-COMPETING CONTINUATION	$511,230
														Subtotal = $511,230

Issue Date FY: 2015 ( Subtotal = $466,600 )
2015	2015	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	6	3/16/2015	COMPETING CONTINUATION	$466,600
														Subtotal = $466,600

Issue Date FY: 2014 ( Subtotal = $0 )
2014	2013	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	5	8/29/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2013 ( Subtotal = $327,916 )
2013	2013	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	5	3/28/2013	NON-COMPETING CONTINUATION	$310,658
2013	2013	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	001	5	5/15/2013	NON-COMPETING CONTINUATION	$17,258
														Subtotal = $327,916

Issue Date FY: 2012 ( Subtotal = $345,175 )
2012	2012	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	4	3/19/2012	NON-COMPETING CONTINUATION	$345,175
														Subtotal = $345,175

Issue Date FY: 2011 ( Subtotal = $345,175 )
2011	2011	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	001	3	6/2/2011	NON-COMPETING CONTINUATION	$24,247
2011	2011	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	3	3/23/2011	NON-COMPETING CONTINUATION	$320,928
														Subtotal = $345,175

Issue Date FY: 2010 ( Subtotal = $356,586 )
2010	2010	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	2	4/23/2010	NON-COMPETING CONTINUATION	$356,586
														Subtotal = $356,586

Issue Date FY: 2009 ( Subtotal = $359,922 )
2009	2009	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	1	5/1/2009	NEW	$359,922
														Subtotal = $359,922

Grand Total All Awards = $7,829,731

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Genetic dissection of auditory circuit assembly

Award Number: R01DC009223

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: 05/15/2009

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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