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Mechanisms of Pro-Resolving Mediators in Periodontal Regeneration

Award Number: R01DE025020
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: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Mechanisms of Pro-Resolving Mediators in Periodontal Regeneration - Dietary supplementation with the n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for improving prevention or outcomes of inflammatory diseases, including periodontitis, has been suggested and supported in the literature. However, there remains a critical need to characterize their mechanism of action to optimize the use of nutritional supplements to benefit the population. There are major gaps in knowledge as it pertains to the mechanisms by which EPA and DHA exert their functional effects. Mechanistically, EPA and DHA supplements in the diet increase the concentration of downstream hydroxylated-EPAs (HEPEs) including 18-HEPE, and hydroxylated-DHAs including 17-HDHA, which are bioactive compounds. 18-HEPE and 17-HDHA are also the precursors for the immunoresolvents known as E-series and D-series resolvins, respectively, which improve periodontal disease outcomes through the activation of specific receptors on stem cells. There remain major gaps in our understanding of the mechanistic relationship between stem cell dysfunction and periodontitis. Our data lead us to the hypothesis that dietary supplementation with EPA and DHA, or their HEPE/HDHA metabolites, will have an impact on treatment outcomes for periodontitis, in part, through the activation of the resolvin/stem cell receptor axis. We will test the hypothesis using a combination of EPA/DHA- and HEPE/HDHA- based dietary supplements in our pig model of stem cell enhanced periodontal regeneration measuring clinical outcomes and investigating mechanism using cutting-edge mass spectrometry-based approaches and assessments of SPM receptor expression and function. Overall, the proposed research will provide much needed clarity to the field of n-3 PUFAs and periodontal disease. The data will specifically provide a scientific rationale for future precision clinical trials with dietary supplements for periodontitis treatment and prevention. The Central Hypothesis is that dietary supplements containing EPA/DHA or HEPE/HDHA precursors of resolvins will enhance resolution of inflammation pathways and mediator production to promote regeneration of the periodontal organ (bone, cementum, and periodontal ligament) by directing stem cell phenotype, proliferation, and differentiation. In this supplement, we will use our ongoing large-animal model experiments to dissect the impact of dietary supplements on the SPM pathways leading to periodontal ligament stem cell control of regeneration. In the miniature pig periodontal regeneration experiments, we will determine whether dietary supplementation with EPA/DHA or concentrated HEPE/HDHA resolvin precursors enhances periodontal regeneration alone or in combination with transplanted, ex vivo expanded miniature pig stem cells and determine the impact of dietary supplementation with EPA/DHA or concentrated HEPE/HDHA resolvin precursors on systemic (blood) and local tissue levels of pro-inflammatory and proresolving lipid mediators. These experiments are critical and focused to determine the potential of dietary supplementation with n-3 PUFAs for periodontal regeneration.


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: 2023 ( Subtotal = $679,847 )
2023	2023	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	001	9	7/18/2023	SUPPLEMENT FOR EXPANSION	$216,722
2023	2023	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	000	9	7/17/2023	NON-COMPETING CONTINUATION	$463,125
														Subtotal = $679,847

Issue Date FY: 2022 ( Subtotal = $458,494 )
2022	2022	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	000	8	7/29/2022	NON-COMPETING CONTINUATION	$458,494
														Subtotal = $458,494

Issue Date FY: 2021 ( Subtotal = $463,125 )
2021	2021	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	000	7	6/25/2021	NON-COMPETING CONTINUATION	$463,125
														Subtotal = $463,125

Issue Date FY: 2020 ( Subtotal = $463,125 )
2020	2020	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	002	6	6/9/2020	NON-COMPETING CONTINUATION	$463,125
2020	2019	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	001	5	4/22/2020	COMPETING CONTINUATION	$59,908
2020	2018	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	000	4	4/22/2020	SUPPLEMENT FOR EXPANSION	-$59,908
														Subtotal = $463,125

Issue Date FY: 2019 ( Subtotal = $486,638 )
2019	2019	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	001	5	6/28/2019	COMPETING CONTINUATION	$486,638
2019	2018	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	002	4	7/11/2019	SUPPLEMENT FOR EXPANSION	$0
2019	2018	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	000	4	6/26/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $486,638

Issue Date FY: 2018 ( Subtotal = $930,625 )
2018	2018	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	001	4	8/27/2018	SUPPLEMENT FOR EXPANSION	$449,250
2018	2018	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	000	4	4/20/2018	NON-COMPETING CONTINUATION	$481,375
														Subtotal = $930,625

Issue Date FY: 2017 ( Subtotal = $476,125 )
2017	2017	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	001	3	5/26/2017	NON-COMPETING CONTINUATION	$47,613
2017	2017	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	000	3	4/28/2017	NON-COMPETING CONTINUATION	$428,512
														Subtotal = $476,125

Issue Date FY: 2016 ( Subtotal = $472,100 )
2016	2016	Forsyth Dental Infirmary for Children Forsyth Institute	140 FENWAY	BOSTON	MA	02115	SUFFOLK	USA	Oral Diseases and Disorders Research	000	2	4/19/2016	NON-COMPETING CONTINUATION	$472,100
														Subtotal = $472,100

Issue Date FY: 2015 ( Subtotal = $495,338 )
2015	2015	Forsyth Dental Infirmary for Children Forsyth Institute	140 FENWAY	BOSTON	MA	02115	SUFFOLK	USA	Oral Diseases and Disorders Research	000	1	4/30/2015	NEW	$495,338
														Subtotal = $495,338

Grand Total All Awards = $4,925,417

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Mechanisms of Pro-Resolving Mediators in Periodontal Regeneration

Award Number: R01DE025020

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: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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