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
- 来源:
- 关键词:Alveolar Bone LossAnaerobic BacteriaB-LymphocytesBacteriaBiological Response ModifiersBone ResorptionContralateralDataDendritic CellsDiabetes MellitusDiabetic mouseDietDisease ProgressionEnzyme-Linked Immunosorbent AssayFlow CytometryGerm-FreeGingival Crevicular FluidGrowthHigh Fat DietHistologicHistologyHomeostasisHyperglycemiaHyperglycemic MiceImmunofluorescence ImmunologicImmunohistochemistryIn VitroInflammationInflammation MediatorsInflammatoryInflammatory ResponseInjectionsInternationalKnock-outKnockout MiceLeukocytesMeasuresMetabolicMetabolic DiseasesMusNon-Insulin-Dependent Diabetes MellitusOralOsteoclastsPathogenesisPathogenicityPatientsPeriodontal DiseasesPeriodontitisPeriodontiumReceptor SignalingReportingRisk FactorsRoleSideSignal TransductionSiteStimulusSuccinatesT-LymphocyteTNFSF11 geneTestingTissuesTopical applicationTumor-infiltrating immune cellsType 2 diabeticWild Type Mouseadaptive immune responsealveolar bonebone losscytokinediabeticdiabetic patientefficacy testingfeedinggut microbiomehistological specimensimmunogenicimmunosuppressive macrophagesin vivometagenomic sequencingmicroCTmicrobialmouse modelneutrophilnoveloral microbial communityoral microbiomeosteoclastogenesisperiodontopathogenprecursor cellpreventprotective effectreceptorresponsetranscriptometranscriptome sequencing
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
2型糖尿病被认为是严重和进展性糖尿病的重要危险因素
牙周炎。糖尿病可能通过代谢失调加速牙周炎,
细菌定植、炎症和骨质丢失的转移。我们最近发现琥珀酸
激活琥珀酸受体(SucnR1),刺激破骨细胞生成和骨吸收。我们的
初步数据进一步显示:(1)龈沟液(GCF)中琥珀酸含量升高
牙周炎患者的牙槽骨高度显著高于牙周炎患者。
牙周炎与T2D;(2)T2D小鼠自发性牙周炎伴有牙周炎升高
牙周组织中琥珀酸水平和胃肠道微生物群改变与正常的比较
小鼠;(3)琥珀酸在体外有利于牙周病原体的生长;(4)外源琥珀酸
增加野生型(WT)的牙周骨丢失;(5)牙周骨丢失
在SucnR1基因敲除小鼠(KO)中得到缓解。目前的提议建立在强有力的基础上
确定琥珀酸升高是否会加速牙周病的初步数据
进步。我们将使用老鼠模型来测试我们的假设,即以琥珀酸为靶点
信号传递可防止牙周病发病加速。在目标1中,我们将使用喂食的小鼠
在正常饮食中,喂食高脂饮食(HFD)的小鼠会变得高血糖,并形成琥珀酸
受体敲除小鼠(SucnR1_KO)确定琥珀酸/SucnR1信号转导
影响正常血糖和高血糖患者的全身反应和改变口腔微生物区系
条件。我们将使用细菌从牙周部位转移到无菌小鼠身上来测试
致病性通过细菌引起的骨丢失来衡量。我们的工作假设是细菌
来自HFD糖尿病小鼠的比来自匹配的正常血糖的细菌会导致更多的骨丢失
控制。在目标2中,我们将确定琥珀酸是否激活SucnR1以增强牙周
炎症刺激引起的骨丢失。在目标3中,我们将确定阻止
破骨前细胞中的琥珀酸信号可减轻牙周组织的骨丢失。我们将使用lysMCre,
SucnR1L/L小鼠模型评估琥珀酸信号是否通过其受体增强
非炎性刺激导致骨丢失。我们还将测试特定SucnR1的有效性
拮抗剂在T2D小鼠自发发展模型中预防牙周炎的作用
牙周炎。我们认为,通过激活SucnR1,琥珀酸具有重要意义
通过描绘这一新的机制,我们将有助于预防
糖尿病患者的牙周骨丢失。
项目成果
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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
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9757747 - 财政年份:2018
- 资助金额:
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