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ATP-purinergic mechanisms underlying noise-induced cochlear synaptopathy and hearing loss

Award Number: R01DC017025
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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SUMMARY The long-term goal of this project is to investigate mechanisms underlying noise-induced cochlear synaptopathy and hidden hearing loss. Noise is a common risk factor for hearing loss. Recent studies have demonstrated that even a single episode of noise overexposure induces transient hearing loss, i.e., temporal threshold shift (TTS), noise-exposed animals could have no hair cell loss but have extensive spiral ganglion neuron (SG) and synapse degeneration. In particular, low spontaneous rate (LSR) auditory nerves and their synaptic connections with inner hair cells are preferentially lost. The noise-exposed animals and humans demonstrate normal hearing threshold and sensitivity (i.e., hidden hearing loss) in the early stage but will eventually exhibit other hearing disorders and hearing loss. Currently, the underlying mechanism for such cochlear synaptopathy remains unclear. Noise stimulates hair cell and neuron over-activation and increases K+ efflux that leads to increasing extracellular K+ concentration. It is well-established that high extracellular K+ can induce toxicity leading to second cell death in the brain following injury and stroke. We hypothesize that high, excess extracellular K+ following noise exposure can also cause SG synapse and neuron degeneration in the cochlea. We previously found that ATP purinergic P2X receptors in the cochlea are required for sinking K+ to re-enter into cells. A recent study also demonstrated that P2X2 receptors are necessary for the development of TTS. In addition, we found that P2X2 mutation can increase susceptibility to noise and induce hearing loss. These studies indicate that P2X receptors may have a critical role in noise-induced cochlear synaptopathy and hidden hearing loss. In this project, we will first test whether high extracellular K+ can cause SG synapse and neuron degeneration (Specific Aim 1, SA1). Then, we will identify and characterize P2X receptor expression in SG neurons, including LSR and HSR (high spontaneous rate) fiber synaptic endings, and test whether P2X receptors can mediate K+-sinking in the SG neurons. In SA3, we will test whether deficiency of P2X receptors can induce and exacerbate cochlear synaptopathy and hearing loss following noise exposure and high-K+ challenge. Completion of these studies will directly reveal the molecular mechanism underlying noise-induced cochlear synaptic degeneration and hidden hearing loss. These novel studies will also open a new therapeutic avenue for targeting noise-induced hearing loss and cochlear synaptopathy.


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 = $0 )
2024	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Research Related to Deafness and Communication Disorders	000	6	1/20/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $1 )
2023	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Research Related to Deafness and Communication Disorders	000	5	12/23/2022	NON-COMPETING CONTINUATION	-$325,125
2023	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Research Related to Deafness and Communication Disorders	001	6	12/27/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$325,126
2023	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Research Related to Deafness and Communication Disorders	004	6	4/17/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$343,644
2023	2021	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Research Related to Deafness and Communication Disorders	003	4	4/17/2023	NON-COMPETING CONTINUATION	-$325,125
2023	2020	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Research Related to Deafness and Communication Disorders	002	3	4/17/2023	NON-COMPETING CONTINUATION	-$18,519
														Subtotal = $1

Issue Date FY: 2022 ( Subtotal = $325,125 )
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Research Related to Deafness and Communication Disorders	000	5	2/11/2022	NON-COMPETING CONTINUATION	$292,612
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Research Related to Deafness and Communication Disorders	001	5	4/21/2022	NON-COMPETING CONTINUATION	$32,513
														Subtotal = $325,125

Issue Date FY: 2021 ( Subtotal = $325,125 )
2021	2021	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Research Related to Deafness and Communication Disorders	000	4	2/12/2021	NON-COMPETING CONTINUATION	$325,125
														Subtotal = $325,125

Issue Date FY: 2020 ( Subtotal = $325,125 )
2020	2020	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Research Related to Deafness and Communication Disorders	000	3	1/31/2020	NON-COMPETING CONTINUATION	$325,125
														Subtotal = $325,125

Issue Date FY: 2019 ( Subtotal = $325,125 )
2019	2019	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Research Related to Deafness and Communication Disorders	000	2	1/25/2019	NON-COMPETING CONTINUATION	$325,125
														Subtotal = $325,125

Issue Date FY: 2018 ( Subtotal = $620,303 )
2018	2018	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Research Related to Deafness and Communication Disorders	001	1	8/16/2018	SUPPLEMENT FOR EXPANSION	$295,178
2018	2018	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Research Related to Deafness and Communication Disorders	000	1	3/22/2018	NEW	$325,125
														Subtotal = $620,303

Grand Total All Awards = $1,920,804

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ATP-purinergic mechanisms underlying noise-induced cochlear synaptopathy and hearing loss

Award Number: R01DC017025

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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