# Targeting Succinate Signaling Impedes Periodontitis Progression

> **NIH NIH R01** · NEW YORK UNIVERSITY · 2022 · $435,884

## Abstract

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.

## Key facts

- **NIH application ID:** 10380813
- **Project number:** 5R01DE027074-05
- **Recipient organization:** NEW YORK UNIVERSITY
- **Principal Investigator:** DANA T GRAVES
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $435,884
- **Award type:** 5
- **Project period:** 2018-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10380813

## Citation

> US National Institutes of Health, RePORTER application 10380813, Targeting Succinate Signaling Impedes Periodontitis Progression (5R01DE027074-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10380813. Licensed CC0.

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