Titanium particle-induced inflammasome activation in the peri-implant mucosal barrier

项目摘要 种植体周围炎是一种口腔黏膜和种植体周围骨骼的炎症性疾病。 在历史上，这种疾病被归因于细菌生物被膜和随后的宿主炎症。 反应，引起种植体周围组织和颌骨破坏。然而，最近的研究结果表明，该版本 种植体中钛的缺乏可能是导致所观察到的猖獗的炎症性骨破坏的重要原因 在种植体周围炎中。支持这一论点的数据包括抗菌治疗缺乏疗效和 大多数流行病学证据表明游离钛的存在与持续的围产期疾病有关。 种植体发炎。更好地了解人类疾病中对钛的免疫反应可以提供信息 努力制定有效的种植体周围炎治疗方案。到目前为止，还没有可靠的危险因素。 种植体炎症治疗可提供种植体周围炎症和颌骨破坏的长期解决。 这项应用将利用以人为中心的临床免疫学模型来研究钛诱导的 炎症可以通过抑制细胞内的蛋白质组装(称为炎症小体)来逆转 放大炎症负担，调节细胞死亡。 拟议的工作将对钛之后的复杂生物级联进行深入研究 通过结合精心挑选的人体样本的临床数据从植入物中溶解微粒 体内研究利用了炎症体抑制的敲除小鼠模型的人群。本研究 提出了两个研究目标：1)评估NLRP3在人外周血中的表达和激活。 2)研究NLRP3介导的上睑下垂在钛相关炎症中的作用。 这项工作的结果将确定钛种植体来源的炎性小体是否被激活 微粒是种植体周围炎症的中心。转化法使用了一只临床前小鼠 该模型是基于携带防止炎症体激活的特定突变的小鼠的可用性。 确定炎症小体抑制是否是钛颗粒介导的可行的分子治疗靶点 种植体周围炎将是确定种植体周围炎治疗靶点的第一个关键步骤。翻译型 这种方法的潜力得到了抑制炎性小体激活的药物的支持，并且 目前正在进行其他炎症条件的临床试验评估。因此，对NLRP3抑制作用的研究 使用小鼠的组织破坏和致病性模型是创新的，因为它为 有潜力优于现有抗菌药物的种植体周围炎的分子治疗 疗效有限、复发率高的治疗方法。这项研究的继续工作将是 随后应用R01进行NLRP3途径的临床前药物开发 使用种植体周围炎临床前模型进行调制，并将其转化为人类原则证明。最终这就是 研究将开发一种解决钛介导的种植体周围炎的最佳药理策略。

Project Summary Peri-implantitis is an inflammatory disease of the oral mucosa and bone surrounding dental implants. Historically, this disease has been attributed to bacterial biofilms and the subsequent host inflammatory response, eliciting peri-implant tissue and jawbone destruction. However, recent findings indicate that release of titanium from implants may significantly contribute to the rampant inflammatory bone destruction observed in peri-implantitis. Data that support this contention include the lack of efficacy of antimicrobial treatments and a preponderance of the epidemiological evidence associating the presence of free titanium to ongoing peri- implant inflammation. A better understanding of immune responses to titanium in human disease can inform efforts to develop efficacious peri-implantitis therapeutic protocols. To date, there are no reliable peri- implantitis treatments to provide long-term resolution of peri-implant inflammation and jawbone destruction. This application will utilize a human-centered, clinical immunology model to investigate if titanium- induced inflammation can be reversed by inhibition of an intracellular protein assembly (known as, inflammasome) that amplifies inflammatory burden and regulates cell death. The proposed work will execute an in-depth investigation of the complex biological cascade that follows titanium microparticle dissolution from implants by coupling clinical data from a carefully selected human sample population with in vivo studies that exploit a knock-out mouse model of inflammasome inhibition. This study proposes two research aims: 1) assess NLRP3 Inflammasome Expression and Activation in Human Peri- implantitis, and 2) investigate the involvement of NLRP3-mediated pyroptosis in Titanium-related inflammation. The outcome of this work will determine if inflammasome activation in response to titanium implant-derived microparticles is central to peri-implant inflammation. The translational approach employs a preclinical mouse model that is based on the availability of mice that carry specific mutations that prevent inflammasome activation. Determining if inflammasome inhibition is a feasible molecular therapeutic target for titanium particle-mediated peri-implantitis will be the first critical step in identifying peri-implantitis therapeutic targets. The translational potential of this approach is supported by the availability of drugs that inhibit inflammasome activation and are currently assessed in clinical trials for other inflammatory conditions. Thus, the investigation of NLRP3 inhibition using a mouse model of tissue destruction and pathogenicity is innovative because it paves the way for molecular therapies of peri-implantitis that have the potential to be superior to the current antimicrobial treatments that demonstrate limited efficacy and high relapse rates. The continuation of this study will be pursued with a subsequent R01 application to conduct preclinical drug development for NLRP3 pathway modulation using peri-implantitis preclinical models and translation to human proof-of-principle. Ultimately this research will develop an optimal pharmacological strategy for resolving titanium-mediated peri-implantitis.