Targeting Succinate Signaling Impedes Periodontitis Progression

靶向琥珀酸信号传导阻止牙周炎进展

基本信息

  • 批准号:
    9882976
  • 负责人:
  • 金额:
    $ 44.48万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-04-01 至 2023-03-31
  • 项目状态:
    已结题

项目摘要

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.
摘要

项目成果

期刊论文数量(0)
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DANA T GRAVES其他文献

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{{ truncateString('DANA T GRAVES', 18)}}的其他基金

Treatment and Mechanisms of Diabetic Fracture Healing
糖尿病骨折愈合的治疗及机制
  • 批准号:
    10595341
  • 财政年份:
    2023
  • 资助金额:
    $ 44.48万
  • 项目类别:
Fibroblast dysregulation promotes dermal eosinophilic/Th2 inflammation
成纤维细胞失调促进真皮嗜酸性/Th2炎症
  • 批准号:
    10725870
  • 财政年份:
    2023
  • 资助金额:
    $ 44.48万
  • 项目类别:
Diabetes reversal and the subgingival microbiota
糖尿病逆转和龈下微生物群
  • 批准号:
    10189550
  • 财政年份:
    2018
  • 资助金额:
    $ 44.48万
  • 项目类别:
Targeting Succinate Signaling Impedes Periodontitis Progression
靶向琥珀酸信号传导阻止牙周炎进展
  • 批准号:
    10380813
  • 财政年份:
    2018
  • 资助金额:
    $ 44.48万
  • 项目类别:
Diabetes reversal and the subgingival microbiota
糖尿病逆转和龈下微生物群
  • 批准号:
    10413264
  • 财政年份:
    2018
  • 资助金额:
    $ 44.48万
  • 项目类别:
Diabetes reversal and the subgingival microbiota
糖尿病逆转和龈下微生物群
  • 批准号:
    9757747
  • 财政年份:
    2018
  • 资助金额:
    $ 44.48万
  • 项目类别:
Dendritic Cells and Periodontal Disease
树突状细胞和牙周病
  • 批准号:
    8664246
  • 财政年份:
    2012
  • 资助金额:
    $ 44.48万
  • 项目类别:
Dendritic Cells and Periodontal Disease
树突状细胞和牙周病
  • 批准号:
    10403515
  • 财政年份:
    2012
  • 资助金额:
    $ 44.48万
  • 项目类别:
Dendritic Cells and Periodontal Disease
树突状细胞和牙周病
  • 批准号:
    8476210
  • 财政年份:
    2012
  • 资助金额:
    $ 44.48万
  • 项目类别:
Dendritic Cells and Periodontal Disease
树突状细胞和牙周病
  • 批准号:
    8868229
  • 财政年份:
    2012
  • 资助金额:
    $ 44.48万
  • 项目类别:

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降解细菌细胞壁的厌氧菌的鉴定与分离
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阐明厌氧菌双歧杆菌的 O2 敏感性机制。
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