Impact of Diabetes hyperglycemia on peri-implantitis

抽象的。 在种植牙植入后的10年内，大约30%的患者发生种植体周围炎， 以种植体周围软组织感染、炎症和骨吸收为特征。相关联的 社会经济负担很重，病人往往患有慢性和令人痛苦的症状。 近年来的研究表明，糖尿病（DM）、高血糖是种植体周围炎的危险因素。然而，在这方面， 尚不清楚高血糖症如何导致种植体周围炎的发病。没有一个明确的认识 的机制和适当的干预，大量的糖尿病患者谁接受种植牙 植入将继续面临发生种植体周围炎的潜在更高风险。我们的初步数据 使用实验性种植体周围炎的小鼠模型证明了不同的口腔微生物组成 在高血糖小鼠与正常血糖小鼠之间观察到，高血糖小鼠显示上调 促炎细胞因子（IL-17和IFN-γ）和更大的种植体周围骨丢失相比，血糖正常 结扎诱导的种植体周围炎后的小鼠。根据文献和我们的初步研究结果，中央 该项目的假设是：1）DM高血糖症通过加重 全身性炎症和2）DM高血糖驱动微生物变化促进植入物周围 炎症和骨质流失。在这个建议中，我们将调查在以下情况下口腔微生物变化的因果关系： 高血糖状况以及这种变化对小鼠中植入物周围炎症和骨丢失的影响。在 目的1，在正常与DM条件下，种植体周围和牙周微生物的变化， 将通过16 S rRNA测序鉴定和表征炎症和高血糖的干预 和宏基因组分析。同一动物种植体周围炎和牙周炎病变中的微生物群分布 将被比较。将确定同一动物的牙龈炎症和骨丢失的相应状态 并在每种条件下进行分析。在目标2中，我们将首先使用体外培养系统来检查响应 通过口腔粘膜上皮细胞和自体脾细胞对来自WT或糖尿病小鼠的植入物周围微生物群的作用 有或没有炎症和高血糖症的干预。然后，将来自WT或 将糖尿病小鼠转移到用抗生素预处理的WT受体小鼠，然后评估 种植体周围炎症和体内骨丢失。为了进一步的机制分析，我们将测试IL-17的作用， 和IFN γ在高血糖相关的种植体周围发病机制中的作用，并描述了在高血糖相关的种植体周围发病机制中的免疫细胞特征。 使用单细胞RNA测序（sc-RNAseq）植入软组织微环境。成功完成 该项目将使我们能够在未来开发更全面的设计和转化方法， 深入了解糖尿病患者种植体周围炎的发病机制。

Abstract. During 10 years after dental implant placement approximately 30% of patients develop peri-implantitis, a disease characterized by soft tissue infection and inflammation and bone resorption around implant. The associated socio-economic burdens are significant, and patients often suffer from the chronic and distressing symptoms. Recent studies suggested that Diabetes mellitus (DM) hyperglycemia is a risk factor of peri-implantitis. However, it is unclear how hyperglycemia contributes to the pathogenesis of peri-implantitis. Without a clear understanding of the mechanism and appropriate intervention, a large number of DM patients who receive dental implant placement will continue to face the potentially higher risk of developing peri-implantitis. Our preliminary data using a murine model of experimental peri-implantitis demonstrated that differential oral microbial compositions were observed between hyperglycemic vs. normoglycemic mice, and hyperglycemic mice showed upregulation of pro-inflammatory cytokines (IL-17 and IFN) and greater peri-implant bone loss compared to normoglycemic mice after ligature-induced peri-implantitis. Based on the literature and our preliminary findings, the central hypothesis for this project is that 1) DM hyperglycemia induces peri-implant dysbiosis through aggravated systemic inflammation, and that 2) DM hyperglycemia-driven microbial changes promote peri-implant inflammation and bone loss. In this proposal, we will investigate the causality of oral microbial change under hyperglycemic condition and the effect of such change on peri-implant inflammation and bone loss in mice. In Aim 1, peri-implant and periodontal microbial changes under normal vs. DM conditions with or without intervention for inflammation and hyperglycemia will be identified and characterized by 16S rRNA sequencing and metagenomic analysis. Microbiota profiles in lesions of peri-implantitis and periodontitis in the same animal will be compared. Respective status of gingival inflammation and bone loss in the same animal will be determined and analyzed under each condition. In Aim 2, we will first use an in vitro culture system to examine the responses by oral mucosal epithelial cells and autogenous splenocytes to peri-implant microbiota from WT or diabetic mice with or without intervention for inflammation and hyperglycemia. Then, peri-implant microbiota from WT or diabetic mice will be transferred to WT recipient mice pre-treated with antibiotics, followed by the assessment of peri-implant inflammation and bone loss in vivo. For further mechanistic analysis, we will test the role of IL-17 and IFN in hyperglycemia-associated peri-implant pathogenesis and characterize immune cell profile in peri- implant soft tissue microenvironment using single cell RNA sequencing (sc-RNAseq). Successful completion of this project will allow us to develop more comprehensive designs and translational approaches in the future to gain insight into peri-implantitis pathogenesis in DM patients.