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粘膜和牙种植体周围骨的炎症性疾病。 历史上，这种疾病被归因于细菌生物膜和随后的宿主炎症反应。 反应，引发种植体周围组织和颌骨破坏。然而，最近的研究结果表明， 植入物中的钛可能显著促进观察到的猖獗的炎性骨破坏， 种植体周围炎支持这一论点的数据包括抗菌治疗缺乏疗效， 流行病学证据的优势将游离钛的存在与正在进行的癌症相关， 植入物炎症。更好地了解人类疾病中对钛的免疫反应可以提供信息 努力开发有效的种植体周围炎治疗方案。到目前为止，还没有可靠的证据- 种植体炎治疗提供种植体周围炎症和颌骨破坏的长期解决方案。 本申请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蛋白质组装（称为炎性体）来逆转， 放大炎症负荷并调节细胞死亡。 拟议的工作将执行一项深入调查的复杂生物级联后，钛 通过结合来自精心选择的人体样本的临床数据， 利用利用炎性小体抑制的敲除小鼠模型进行体内研究。本研究 提出了两个研究目标：1）评估NLRP 3炎症体在人类周围组织中的表达和激活， 植入物炎，和2）研究NLRP 3介导的焦亡在钛相关炎症中的参与。 这项工作的结果将确定炎症小体激活是否对钛植入物源性 微粒是植入物周围炎症的核心。转化方法采用临床前小鼠 该模型基于携带防止炎性小体激活的特定突变的小鼠的可用性。 确定炎性小体抑制是否是钛颗粒介导的一种可行的分子治疗靶点 种植体周围炎将是鉴定种植体周围炎治疗靶点的第一个关键步骤。平移 这种方法的潜力得到了抑制炎性小体活化的药物的可用性的支持， 目前在临床试验中评估其他炎症状况。因此，NLRP 3抑制的研究 使用组织破坏和致病性的小鼠模型是创新的，因为它为 种植体周围炎的分子疗法有可能上级目前的抗微生物药物 这些治疗显示出有限的疗效和高复发率。这项研究的继续将是 随后进行R 01申请，以进行NLRP 3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节并转化为人类原理验证。最终这 研究将开发用于解决钛介导的种植体周围炎的最佳药理学策略。

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.