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Epigenetic and non-epigenetic role of SIRT1 in fluoride-induced cell stress.

Award Number: R01DE027648
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Epigenetic and non-epigenetic role of SIRT1 in fluoride-induced cell stress. - The goal of this application is to characterize epigenetic and non-epigenetic functions of SIRT1 in adaptive responses during dental fluorosis. Fluoride is an effective caries prophylactic, however chronic over-exposure can result in dental fluorosis. More than 30% of children in the U.S. suffer from dental fluorosis. Our ultimate goal is to develop novel strategies that prevent or reduce dental fluorosis while keeping the benefit of prophylactic public water fluoridation to prevent caries. Recently we reported that fluoride activates SIRT1 and autophagy as an adaptive response to protect cells from cell stress. It is known that SIRT1 deacetylates histones to repress gene expression (epigenetic deacetylation). SIRT1 also deacetylates a number of non-histone proteins (non-epigenetic deacetylation) functioning in the regulation of autophagy, mitochondria metabolism, cell survival and organismal lifespan. However, the exact functions of SIRT1 and its downstream targets in dental fluorosis are unknown. Our goal in this proposal is to identify how SIRT1 functions in fluoride-induced stress responses and to find appropriate targets that could be modulated pharmacologically for the treatment of dental fluorosis. Our central hypothesis is that SIRT1 can play protective roles by intiating autophagy and regulating epigenetics in dental fluorosis. To test our hypothesis we propose three specific AIMs. AIM 1. Identify SIRT1 non-histone targets in ameloblast-derived cells treated with fluoride in vitro. AIM 2. Identify SIRT1 histone targets in ameloblast-derived cells treated with fluoride in vitro. AIM 3. Determine if SIRT1 over expression or conditional knockout effects enamel development and dental fluorosis in vivo. To attain these AIMs, we will use SIRT1 overexpressor and knockout ameloblast-like cells LS8 (LS8 Sirt1/over and LS8Sirt1/KO cells) established by the CRISPR/Cas9 technology in vitro. We will analyze the role of SIRT1 using SIRT1 over expressing mice (SIRT1super) and conditional knockout mice (SIRT1cKO) in vivo. Once epigenetic and non-epigenetic SIRT1 function in enamel pathophysiology is revealed, it may be possible to develop novel strategies to pharmacologically manipulate SIRT1 function to prevent dental fluorosis.


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 = $0 )
2025	2023	NOVA SOUTHEASTERN UNIVERSITY, INC	3300 S UNIVERSITY DR	FT LAUDERDALE	FL	33328	BROWARD	USA	Oral Diseases and Disorders Research	000	6	5/22/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $68,700 )
2024	2024	NOVA SOUTHEASTERN UNIVERSITY, INC	3300 S UNIVERSITY DR	FT LAUDERDALE	FL	33328	BROWARD	USA	Oral Diseases and Disorders Research	004	6	5/30/2024	SUPPLEMENT FOR EXPANSION	$68,700
2024	2023	NOVA SOUTHEASTERN UNIVERSITY, INC	3300 S UNIVERSITY DR	FT LAUDERDALE	FL	33328	BROWARD	USA	Oral Diseases and Disorders Research	003	6	2/23/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$874,673
2024	2022	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Oral Diseases and Disorders Research	002	5	2/23/2024	NON-COMPETING CONTINUATION	-$360,850
2024	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Oral Diseases and Disorders Research	001	4	2/23/2024	NON-COMPETING CONTINUATION	-$364,700
2024	2020	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Oral Diseases and Disorders Research	000	3	2/23/2024	NON-COMPETING CONTINUATION	-$149,123
														Subtotal = $68,700

Issue Date FY: 2023 ( Subtotal = $57,493 )
2023	2023	NOVA SOUTHEASTERN UNIVERSITY, INC.	3301 COLLEGE AVE	FORT LAUDERDALE	FL	33314	BROWARD	USA	Oral Diseases and Disorders Research	004	6	6/16/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$364,493
2023	2022	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Oral Diseases and Disorders Research	003	5	6/15/2023	NON-COMPETING CONTINUATION	$0
2023	2018	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Oral Diseases and Disorders Research	000	1	1/20/2023	NEW	$0
2023	2018	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Oral Diseases and Disorders Research	002	1	4/19/2023	NEW	$0
2023	2018	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Oral Diseases and Disorders Research	001	1	3/13/2023	NEW	-$307,000
														Subtotal = $57,493

Issue Date FY: 2022 ( Subtotal = $360,850 )
2022	2022	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Oral Diseases and Disorders Research	000	5	5/20/2022	NON-COMPETING CONTINUATION	$360,850
														Subtotal = $360,850

Issue Date FY: 2021 ( Subtotal = $364,700 )
2021	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Oral Diseases and Disorders Research	000	4	5/20/2021	NON-COMPETING CONTINUATION	$364,700
														Subtotal = $364,700

Issue Date FY: 2020 ( Subtotal = $370,753 )
2020	2020	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Oral Diseases and Disorders Research	000	3	5/15/2020	NON-COMPETING CONTINUATION	$370,753
														Subtotal = $370,753

Issue Date FY: 2019 ( Subtotal = $307,001 )
2019	2019	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Oral Diseases and Disorders Research	000	2	4/22/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$307,001
														Subtotal = $307,001

Issue Date FY: 2018 ( Subtotal = $379,060 )
2018	2018	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Oral Diseases and Disorders Research	000	1	5/30/2018	NEW	$379,060
														Subtotal = $379,060

Grand Total All Awards = $1,908,557

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Epigenetic and non-epigenetic role of SIRT1 in fluoride-induced cell stress.

Award Number: R01DE027648

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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