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Mechanism and Functional Significance of Polarity Reversal in Mechanosensory Organs

Award Number: R01DC018304
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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Mechanism and Functional Significance of Polarity Reversal in Mechanosensory Organs - PROJECT SUMMARY/ABSTRACT Vestibular disorders affect as many as 35% of adults past age 40. Studies of the vestibular inner ear have yielded important insights into how we process and compensate for head motion including the existence of parallel channels of information in the afferent nerve. In macular organs, for example, two populations of hair cells adopt opposite planar orientations of their hair bundles and thus opposite responses to head movements. This highly conserved bidirectional organization was first described in neuromasts, the lateral line organs sensing water movements in fish, but the genetic program implementing this reversal during development is only starting to be deciphered. Consequently, ablation studies to reveal the importance of reversal for vestibular function have not been possible until recently. Here we propose to address this question by investigating the consequences of inactivating an orphan G protein coupled receptor (GPCRx), implicated by our preliminary data in orientation reversal in mouse hair cell epithelia. Based on our preliminary data, we suggest that mouse GPCRx functions downstream of the transcription factor EMX2 and upstream of the heterotrimeric G protein Gi to reverse a ground state of polarity established by planar cell polarity proteins. We will test this hypothesis and also use the GPCRx mutant as an animal model to pinpoint how polarity reversal shapes macular organ responses and downstream effects on vestibular behaviors. To reach these goals, we will: 1) Use genetics to determine how GPCRx instructs reversal at the molecular level, solving its epistatic relationship to EMX2, Gi and planar cell polarity proteins in mice, and use zebrafish to test whether GPCRx-Gi is a conserved effector pathway for reversal. 2) Use molecular markers, electrophysiology and calcium imaging to resolve hair cell maturation and function in absence of polarity reversal. 3) Determine how polarity reversal affects afferents' organization and function, with afferent recordings, as well as overall vestibular function using behavioral tests. Our coherent body of preliminary evidence ensures the feasibility and the high interest of the project, and our focus on a virtually unstudied receptor protein guarantees innovation. The multi-PI team is ideally suited to address complementary questions in both the mouse and zebrafish acoustico-lateralis systems. We anticipate that this collaborative effort will be decisive towards solving the mechanism of hair cell orientation reversal, its conservation across vertebrates and its significance for mammalian vestibular physiology. Thorough understanding of polarity reversal will help interpret and design treatments for vestibular dysfunctions.


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 = $689,660 )
2024	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Research Related to Deafness and Communication Disorders	001	5	5/3/2024	NON-COMPETING CONTINUATION	$68,966
2024	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Research Related to Deafness and Communication Disorders	000	5	11/15/2023	NON-COMPETING CONTINUATION	$620,694
														Subtotal = $689,660

Issue Date FY: 2023 ( Subtotal = $691,725 )
2023	2023	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Research Related to Deafness and Communication Disorders	000	4	11/18/2022	NON-COMPETING CONTINUATION	$622,552
2023	2023	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Research Related to Deafness and Communication Disorders	001	4	1/13/2023	NON-COMPETING CONTINUATION	$69,173
														Subtotal = $691,725

Issue Date FY: 2022 ( Subtotal = $699,428 )
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Research Related to Deafness and Communication Disorders	001	3	4/21/2022	NON-COMPETING CONTINUATION	$69,943
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Research Related to Deafness and Communication Disorders	000	3	11/19/2021	NON-COMPETING CONTINUATION	$629,485
														Subtotal = $699,428

Issue Date FY: 2021 ( Subtotal = $698,280 )
2021	2021	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Research Related to Deafness and Communication Disorders	001	2	1/8/2021	NON-COMPETING CONTINUATION	$69,827
2021	2021	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Research Related to Deafness and Communication Disorders	000	2	11/19/2020	NON-COMPETING CONTINUATION	$628,453
														Subtotal = $698,280

Issue Date FY: 2020 ( Subtotal = $743,873 )
2020	2020	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Research Related to Deafness and Communication Disorders	001	1	11/20/2019	NEW	$0
2020	2020	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Research Related to Deafness and Communication Disorders	000	1	11/18/2019	NEW	$743,873
														Subtotal = $743,873

Grand Total All Awards = $3,522,966

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Mechanism and Functional Significance of Polarity Reversal in Mechanosensory Organs

Award Number: R01DC018304

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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