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Defining gene expression and regulation in lingual taste and non-taste papilla epithelium

Award Number: R21DC017799
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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Defining gene expression and regulation in lingual taste and non-taste papilla epithelium - Abstract The tongue is a heterogeneous tissue that comprises taste fungiform papillae (FP) and non-taste filiform papillae (FILIF) in the anterior region. Maintenance of FP and FILIF requires tight regulation of basal epithelial cell renewal and subsequent proper differentiation. The basal epithelia of FP and FILIF differentiate into distinct sub-sites of the tongue, suggesting significant differences in gene regulation. Understanding the genes that regulate the maintenance of these distinct taste and non-taste epithelia will provide fundamental insight into the mechanisms that control tongue function. Our data establish that Hedgehog (HH) signaling in epithelial cells is essential for adult FP maintenance. Strikingly, within the epithelium, expression of the HH transcriptional effector and target gene, Gli1, is restricted to the FP, while the related transcription factor and key HH pathway component, Gli2 is expressed in the entire basal lingual epithelium, including FP and FILIF. Although we have demonstrated an essential role for epithelial Gli2 in FP maintenance, there remains a major gap in understanding how GLI2 regulates FP homeostasis. Further, while essential for many oral functions, non-taste FILIF homeostasis remains understudied. We hypothesize that FP and FILIF epithelia have distinct gene profiles that differentially regulate lingual tissue homeostasis. We will use Gli1 reporters to efficiently distinguish between taste and non-taste epithelia. In Aim 1 we will discover differentially expressed genes and their regulation by HH signaling in the FP and FILIF epithelial cell populations employing RNA-seq simultaneously with GLI2 ChIP-seq, using a novel FLAG-tagged knock-in Gli2 allele. Our published data show that inhibition of HH signaling using the cancer drug sonidegib is sufficient to drive taste organ and sensation loss whereas the non-taste FILIF remain intact. Notably, patients who take sonidegib report severe taste dysgeusia and ageusia. Building on studies to understand the mechanisms of taste alteration after pharmacological inhibition of HH pathway, we will determine deregulated genes and their function. Although expression of Gli1 is eliminated after sonidegib treatment, our preliminary data indicate that Gli2 expression is retained in the FP epithelium. In Aim 2, to understand the exact effects of HH pathway blockade and role of active Gli2 in FP and FILIF, we will rely on similar experimental approaches combining RNA-seq and GLI2 ChIP-seq. The data obtained will help to understand and illustrate mechanisms that underlie taste disruptions in patients receiving HH pathway inhibitor drugs and may lead to identification of novel targets for development of therapeutic approaches. Principally, defining gene expression and regulation in the distinct taste (Gli1+;Gli2+) and non-taste (Gli1-;Gli2+) epithelia will confer advanced knowledge about the mechanisms of tongue homeostasis. Overall, this proposal will lay the foundation for an in-depth understanding of the genetic, molecular and functional architecture of the FP and FILIF basal epithelium and HH signaling regulation in these particular taste and non-taste lingual environments.


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 = -$5,387 )
2024	2021	RU SCHOOL OF OSTEOPATHIC MEDICINE	42 E LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Research Related to Deafness and Communication Disorders	000	4	8/14/2024	NON-COMPETING CONTINUATION	-$5,387
														Subtotal = -$5,387

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	RU SCHOOL OF OSTEOPATHIC MEDICINE	42 E LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Research Related to Deafness and Communication Disorders	000	4	5/1/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $161,000 )
2021	2021	RU SCHOOL OF OSTEOPATHIC MEDICINE	42 E LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Research Related to Deafness and Communication Disorders	000	4	4/7/2021	NON-COMPETING CONTINUATION	$161,000
														Subtotal = $161,000

Issue Date FY: 2020 ( Subtotal = $164,150 )
2020	2020	RU SCHOOL OF OSTEOPATHIC MEDICINE	42 E LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Research Related to Deafness and Communication Disorders	002	3	4/17/2020	NON-COMPETING CONTINUATION	$161,000
2020	2019	RU SCHOOL OF OSTEOPATHIC MEDICINE	42 E LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Research Related to Deafness and Communication Disorders	004	2	5/13/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$16,051
2020	2019	RU SCHOOL OF OSTEOPATHIC MEDICINE	42 E LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Research Related to Deafness and Communication Disorders	001	2	3/18/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$101,430
2020	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Research Related to Deafness and Communication Disorders	000	1	3/17/2020	NEW	-$98,280
2020	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Research Related to Deafness and Communication Disorders	003	1	5/13/2020	NEW	-$16,051
														Subtotal = $164,150

Issue Date FY: 2019 ( Subtotal = $156,000 )
2019	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Research Related to Deafness and Communication Disorders	000	1	3/8/2019	NEW	$156,000
														Subtotal = $156,000

Grand Total All Awards = $475,763

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Defining gene expression and regulation in lingual taste and non-taste papilla epithelium

Award Number: R21DC017799

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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