Targeting Succinate Signaling Impedes Periodontitis Progression

摘要 2型糖尿病被认为是一个重要的危险因素， 牙周炎糖尿病可通过代谢失调加速牙周炎， 细菌定植、炎症和骨丢失的变化。我们最近发现琥珀酸 激活琥珀酸受体（SucnR 1），刺激破骨细胞生成和骨吸收。我们 初步数据进一步显示：（1）龈沟液（GCF）中琥珀酸水平升高 牙周炎患者和升高的患者， （2）T2 D小鼠自发性牙周炎伴高水平的 牙周组织中的琥珀酸水平和胃肠道微生物组的改变与正常相比 小鼠;（3）琥珀酸促进牙周致病菌的体外生长;（4）外源性琥珀酸 增强野生型（WT）的牙周骨损失;和（5）牙周骨损失是 在SucnR 1敲除小鼠（KO）中减轻。目前的建议是建立在强大的 确定琥珀酸盐升高是否加速牙周病的初步数据 进展我们将使用小鼠模型来测试我们的假设， 信号传导防止加速牙周病发病。在目标1中，我们将使用喂食 在正常饮食中，喂食高脂饮食（HFD）的小鼠会出现高血糖，而琥珀酸盐 受体敲除小鼠（SucnR1_KO），以确定琥珀酸/SucnR 1信号传导是否 影响全身反应并改变正常和高血糖患者的口腔微生物群 条件我们将使用从牙周部位转移到无菌小鼠的细菌来测试 通过细菌引起的骨丢失测量致病性。我们的假设是细菌 来自HFD糖尿病小鼠的细菌将比来自匹配的血糖正常小鼠的细菌诱导更多的骨丢失。 对照在目标2中，我们将确定琥珀酸盐是否激活SucnR 1以增强牙周炎。 炎症刺激引起的骨丢失。在目标3中，我们将确定 前破骨细胞中的琥珀酸信号传导促进牙周组织骨丢失。我们将使用lysMCre， SucnR 1 L/L小鼠模型，以评估琥珀酸信号传导是否通过其受体增强 非炎性刺激诱导骨丢失。我们还将测试一种特定SucnR 1 拮抗剂在预防自发发展的T2 D小鼠模型中的牙周炎中的作用 牙周炎我们认为，通过激活SucnR 1，琥珀酸具有重要意义， 牙周病，并通过描绘这种新的机制，我们将有助于预防 糖尿病患者的牙周骨丢失。

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.