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

钛颗粒诱导种植体周围粘膜屏障炎症小体激活

基本信息

批准号：
10218850
负责人：
Georgios Kotsakis
金额：
$ 23.18万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10218850
关键词：
Affect Alveolar Bone Loss Bacteria Biocompatible Materials Biological Bone Marrow CASP1 gene CD14 gene Caspase Inhibitor Cell Death Chronic Clinical Clinical Data Clinical Immunology Clinical Trials Complex Coupling Data Dental Dental Implants Dentistry Disease Environment Epidemiology Etiology Exhibits Feedback Foundations Fusobacterium nucleatum Grant Human Immune response Implant Inflammasome Inflammation Inflammatory Inflammatory Response Innate Immune Response Interleukin-1 beta Investigation Knockout Mice Lead Link Lytic Mediating Medical Microbial Biofilms Modeling Molecular Mouth Diseases Mucositis Mucous Membrane Mus Mutation Oral Oral mucous membrane structure Outcome Pathogenicity Pathway interactions Patients Periodontitis Persons Pharmaceutical Preparations Pharmacology Play Population Pre-Clinical Model Preclinical Drug Development Proteins Protocols documentation Relapse Research Resolution Role Safety Sampling Shapes Signal Transduction Site Therapeutic Time Tissue Model Tissues Titanium Tooth structure Validation Work antimicrobial base bone bone loss clinically relevant early onset effective therapy efficacious treatment experimental study human disease in vivo inflammatory bone loss inhibitor/antagonist innovation interleukin-1beta-converting enzyme inhibitor macrophage molecular targeted therapies monocyte mouse model oral bacteria oral tissue particle pathogenic bacteria peri-implant bone loss peri-implantitis pre-clinical prevent public health relevance response screening targeted treatment therapeutic target translation to humans translational approach treatment strategy

项目摘要

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.

项目摘要植入物炎是口腔粘膜和骨骼周围牙齿植入物的一种炎症性疾病。从历史上看，该疾病一直归因于细菌生物膜和随后的宿主炎症反应，引起种植体周围组织和颚骨破坏。但是，最近的发现表明该发布植入物的钛可能会显着有助于观察到的炎症骨骼破坏在植入植入术中。支持此争论的数据包括缺乏抗菌治疗的功效和占优势的流行病学证据，将游离钛的存在与持续的周期相关联植入炎症。更好地了解人类疾病中对钛的免疫反应可以告知制定有效的植入植入术治疗方案的努力。迄今为止，还没有可靠的周期植入炎治疗可长期解决植入物周围的炎症和颚骨破坏。该应用将利用以人为中心的临床免疫学模型来研究钛是否引起炎症可以通过抑制细胞内蛋白质组件（称为炎症体）来逆转，放大炎症负担并调节细胞死亡。拟议的工作将对钛的复杂生物级联反应进行深入调查通过从精心选择的人类样品中耦合临床数据，微粒从植入物中溶解具有体内研究的种群，可利用炎症抑制的敲除小鼠模型。这项研究提出了两个研究目的：1）评估人周日的NLRP3炎性体表达和激活植入炎和2）研究NLRP3介导的凋亡在与钛相关的炎症中的参与。这项工作的结果将确定是否响应于钛植入物来源的炎性体激活微粒是植入物周围炎症的中心。翻译方法采用临床前鼠标基于携带特定突变的小鼠的可用性模型，以防止炎症体激活。确定炎性体抑制是否是可行的分子治疗靶标的钛颗粒介导的植入体炎将是识别植入植入术治疗靶点的第一步。翻译这种方法的潜力得到了抑制炎症体激活的药物的可用性的支持，并且目前在临床试验中针对其他炎症状况进行了评估。因此，NLRP3抑制作用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，具有优于当前抗菌剂的潜力证明有限疗效和高复发率的治疗方法。这项研究的继续是随后的R01应用程序进行NLRP3途径的临床前药物开发使用种植体植入体临床前模型的调节，并将其转化为人类原则证明。最终研究将制定一种解决钛介导的植入物炎的最佳药理策略。