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Identification and characterization of novel functions for the Usher proteins in the inner ear

Award Number: R01DC021070
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: 05/01/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Identification and characterization of novel functions for the Usher proteins in the inner ear - ABSTRACT. An organism’s perception of its surrounding environment depends on the sensory function. Neurosensory cells from the inner ear are involved in key biological processes associated with hearing and balance. To be able to achieve their function these cells depend on a complex array of membrane receptors, ion channels, and signaling molecules that are concentrated at extremely sophisticated structures positioned at the apical (hair cell bundle and kinocilium) and basal (ribbon synapses) poles. Disruption of this network due, for example, to mutations, results in morphological and functional abnormalities and forms the bases of many human genetic disorders. This proposal is focused on studying the role of the Pcdh15-Itga8 (Protocadherin-15-Integrin alpha8) complex during hair cell (HC) development and function, and the downstream signaling pathways activated by it. Our recently published work and preliminary data suggest that the absence of Pcdh15-Itga8 complex results in HC bundle abnormalities, increase the number of outer hair cells, and alterations in the Rhoa-ERM(Ezrin-Radixin-Moesin)-Yap signaling cascade. Moreover, Itga8 hair cell-specific conditional knockout mice have progressive hearing loss and sensibility to noise exposure. Based on this information, our central hypothesis is that during inner ear development, environmental cues activate the Itga8-Pcdh15 complex resulting in the modulation of cytoskeletal elements that will activate downstream signaling cascades. Lack of the complex results in inner ear abnormalities that over time can cause progressive hearing loss. We will test this hypothesis with two specific aims. In the first aim, we will identify the environmental cues that lead to Pcdh15-Itga8 activation and the formation of cytoskeletal structures. We will also identify and characterize the complex’s molecular targets. In the second aim, we will investigate the contribution of supporting cells and spiral ganglion neurons to the Pcdh15-Itga8 complex phenotype and the sensibility to noise. Collectively the studies proposed here will clarify the functional role(s) for the Pcdh15-Itga8 complex during organ of Corti development, introducing a direct functional link between Usher syndrome and an integrin-downstream signaling cascade.


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 = -$63,266 )
2025	2024	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	000	2	5/23/2025	TERMINATION	$0
2025	2024	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	001	2	8/19/2025	TERMINATION	-$63,266
														Subtotal = -$63,266

Issue Date FY: 2024 ( Subtotal = $491,052 )
2024	2024	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	000	2	5/9/2024	NON-COMPETING CONTINUATION	$491,052
														Subtotal = $491,052

Issue Date FY: 2023 ( Subtotal = $520,111 )
2023	2023	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	000	1	4/27/2023	NEW	$520,111
														Subtotal = $520,111

Grand Total All Awards = $947,897

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Identification and characterization of novel functions for the Usher proteins in the inner ear

Award Number: R01DC021070

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: 05/01/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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