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Neural and genetic mechanisms underlying mechanosensation in C. elegans

Award Number: R01DC018167
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: 12/05/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2030

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Neural and genetic mechanisms underlying mechanosensation in C. elegans - Mechanical cues, such as sound, touch, gravity, and shear stress, activate mechanosensory neurons/cells that mediate mechanosensory modalities such as hearing, touch, proprioception, shear stress sensation, and blood pressure regulation. A central player in mechanosensation is the mechanotransduction channels that sense mechanical forces and transduce them into electrical outputs. Among the six primary sensory modalities, auditory sensation or hearing is unique in that it is only found in vertebrates and some insects. The vast majority of invertebrate species are thus considered insensitive to sound. We recently challenged this conventional view by showing that C. elegans senses airborne sound at frequencies between 100 Hz and 5 kHz. Sound vibrates the worm skin that acts as a pressure-to-displacement transducer similar to vertebrate eardrum, activates sound-sensitive neurons attached to the skin, and evokes phonotaxis behavior. Thus, the ability to sense sound is not restricted to vertebrates and insects as previously thought. Our work also developed C. elegans as a new model for studying auditory sensation. To interrogate the underlying genetic mechanisms, we conducted a large genetic screen for genes regulating auditory sensation in C. elegans. We found that the nAChR DES-2/DES-3, an ACh-gated cation channel, transduces sound signals in sound- sensitive neurons and does so independently of ACh. Our genetic screen also identified several other genes, such as pnpt-1, whose human homolog PNPT1 has been identified as a nonsyndromic deafness gene with an unknown etiology. These findings uncover a novel, unexpected function of nAChRs in mechanosensation, suggesting that nAChRs may participate in the formation of a novel mechanotransduction channel. In addition, the identification of a conserved role of pnpt-1/PNPT1 in both C. elegans and human auditory sensation reveals the presence of similarities in genetic mechanisms underlying auditory sensation across phyla. Thus, investigating auditory sensation in C. elegans will help characterize not only those mechanisms conserved across phyla (e.g. pnpt-1/PNPT1), but also phylum-specific mechanisms (e.g. nAChRs), the latter of which may lead to the identification of novel mechanotransduction channels mediating other mechanosensory modalities in mammals, such as touch, proprioception, shear stress sensation, blood pressure regulation, etc. Despite these exciting findings, many unanswered questions remain. For example, the molecular composition of the mechanotransduction channel mediating auditory sensation in C. elegans remains unclear. In addition, though we identified a key role for pnpt-1PNPT1 in auditory sensation, the underlying mechanisms remain elusive. We will address these questions in the current proposal using a multidisciplinary approach combining molecular genetics, behavioral analysis, calcium imaging and electrophysiology. The proposed work will not only provide novel insights into auditory sensation but also mechanosensation as a whole.


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	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Research Related to Deafness and Communication Disorders	000	6	1/26/2026	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $468,236 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Research Related to Deafness and Communication Disorders	001	6	7/31/2025	COMPETING CONTINUATION	$468,236
2025	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Research Related to Deafness and Communication Disorders	000	5	3/31/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $468,236

Issue Date FY: 2024 ( Subtotal = $344,810 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Research Related to Deafness and Communication Disorders	000	5	11/15/2023	NON-COMPETING CONTINUATION	$310,329
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Research Related to Deafness and Communication Disorders	001	5	5/7/2024	NON-COMPETING CONTINUATION	$34,481
														Subtotal = $344,810

Issue Date FY: 2023 ( Subtotal = $354,092 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Research Related to Deafness and Communication Disorders	001	4	1/12/2023	NON-COMPETING CONTINUATION	$35,409
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Research Related to Deafness and Communication Disorders	000	4	11/15/2022	NON-COMPETING CONTINUATION	$318,683
														Subtotal = $354,092

Issue Date FY: 2022 ( Subtotal = $363,374 )
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Research Related to Deafness and Communication Disorders	001	3	4/19/2022	NON-COMPETING CONTINUATION	$36,338
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Research Related to Deafness and Communication Disorders	000	3	11/22/2021	NON-COMPETING CONTINUATION	$327,036
														Subtotal = $363,374

Issue Date FY: 2021 ( Subtotal = $372,656 )
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Research Related to Deafness and Communication Disorders	001	2	1/7/2021	NON-COMPETING CONTINUATION	$37,266
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Research Related to Deafness and Communication Disorders	000	2	11/24/2020	NON-COMPETING CONTINUATION	$335,390
														Subtotal = $372,656

Issue Date FY: 2020 ( Subtotal = $381,938 )
2020	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Research Related to Deafness and Communication Disorders	000	1	12/3/2019	NEW	$381,938
														Subtotal = $381,938

Grand Total All Awards = $2,285,106

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Neural and genetic mechanisms underlying mechanosensation in C. elegans

Award Number: R01DC018167

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: 12/05/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2030

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