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Targeting Succinate Signaling Impedes Periodontitis Progression

Award Number: R01DE027074
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: 04/01/2018
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Targeting Succinate Signaling Impedes Periodontitis Progression - Abstract Type 2 Diabetes is recognized as an important risk factor for more severe and progressive periodontitis. Diabetic condition may accelerate periodontitis through metabolic dysregulation, shift in bacterial colonization, inflammation, and bone loss. We recently found that succinate activates succinate receptor (SucnR1) to stimulate osteoclastogenesis and bone resorption. Our preliminary data further show (1) succinate was elevated in the gingival crevicular fluid (GCF) from periodontitis patients and the elevation was significantly greater in patients with both periodontitis and T2D; (2) spontaneous periodontitis in T2D mice was accompanied by elevated succinate levels in the periodontium and altered gastrointestinal microbiome compare to normal mice; (3) succinate favors the growth of periodontal pathogens in vitro; (4) exogenous succinate enhances periodontal bone loss in wild type (WT); and (5) the periodontal bone loss is mitigated in SucnR1 knock out mice (KO) mice. The current proposal is built on strong preliminary data to determine whether succinate elevation accelerates periodontal disease progression. We will employ mouse models to test our hypotheses that targeting succinate signaling prevents accelerated periodontal disease pathogenesis. In Aim 1 we will use mice fed on normal diet, mice fed on High Fat Diet (HFD) which become hyperglycemic, and succinate receptor knock out mice (SucnR1_KO) to determine whether succinate/SucnR1 signaling influences systemic response and alters oral microbiota in normal and hyperglycemia conditions. We will use bacterial transfer from the periodontal site to germ free mice to test the pathogenicity as measured by bacteria-induced bone loss. Our working hypothesis is bacteria from HFD diabetic mice will induce more bone loss than bacteria from matched normoglycemic controls. In Aim 2 we will determine whether succinate activates SucnR1 to enhance periodontal bone loss stimulated by inflammation stimulus. In Aim 3 we will determine whether blocking succinate signaling in pre-osteoclasts alleviates periodontium bone loss. We will use lysMCre, SucnR1L/L mouse model to assess whether succinate signaling through its receptor to enhance non-inflammatory stimuli induced bone loss. We will also test the efficacy of a specific SucnR1 antagonist in preventing periodontitis in a T2D mouse model that spontaneously develop periodontitis. We propose that via activation of SucnR1, succinate has significant implications in periodontal disease and by delineating this novel mechanism, we will help to prevent periodontal bone loss in diabetic patients.


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 = $0 )
2024	2022	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Oral Diseases and Disorders Research	001	5	6/3/2024	NON-COMPETING CONTINUATION	$0
2024	2022	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Oral Diseases and Disorders Research	000	5	3/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $435,884 )
2022	2022	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Oral Diseases and Disorders Research	001	5	4/21/2022	NON-COMPETING CONTINUATION	$39,628
2022	2022	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Oral Diseases and Disorders Research	000	5	2/21/2022	NON-COMPETING CONTINUATION	$396,256
														Subtotal = $435,884

Issue Date FY: 2021 ( Subtotal = $434,324 )
2021	2021	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Oral Diseases and Disorders Research	000	4	3/31/2021	NON-COMPETING CONTINUATION	$434,324
														Subtotal = $434,324

Issue Date FY: 2020 ( Subtotal = $444,805 )
2020	2020	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Oral Diseases and Disorders Research	000	3	3/4/2020	NON-COMPETING CONTINUATION	$444,805
														Subtotal = $444,805

Issue Date FY: 2019 ( Subtotal = $452,248 )
2019	2019	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Oral Diseases and Disorders Research	000	2	2/28/2019	NON-COMPETING CONTINUATION	$452,248
														Subtotal = $452,248

Issue Date FY: 2018 ( Subtotal = $849,082 )
2018	2018	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Oral Diseases and Disorders Research	000	1	2/20/2018	NEW	$474,261
2018	2018	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Oral Diseases and Disorders Research	001	1	8/27/2018	SUPPLEMENT FOR EXPANSION	$374,821
														Subtotal = $849,082

Grand Total All Awards = $2,616,343

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Targeting Succinate Signaling Impedes Periodontitis Progression

Award Number: R01DE027074

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: 04/01/2018

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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