Novel mechanisms and 'complement-ary' therapy in periodontitis

描述（由申请人提供）：牙周炎的新机制和“补充”治疗项目概述牙周炎影响大多数成年人，而估计有10-15%的人发展为严重的牙周炎，对患者产生全身影响（例如，增加动脉粥样硬化和糖尿病的风险）。然而，在分子水平上对潜在的免疫病理知之甚少，缺乏有效的、精确靶向的局部治疗方法。临床和组织学观察以及实验研究表明，牙周炎与补体系统有关。然而，各种补体途径在牙周炎中的确切作用尚未确定。因此，目前尚不确定需要阻断哪些特定途径或成分来减轻炎症病理，或者保持完整以支持宿主防御。在第一阶段，这种机械性和介入性方法需要使用适当的临床前动物模型。本建议的总体目标是弥合目前补体参与牙周炎的机制缺陷，以允许有针对性的干预。拟议的项目涉及路易斯维尔大学牙科学院和宾夕法尼亚大学医学院之间的联盟安排，并汇集了牙周炎症，微生物免疫逃避和补充靶向治疗领域的领先，互补和综合专业知识。在Aim 1中，提出了一种系统的方法来分析已经在初步研究中涉及的集中或源自中央补体枢纽（C3, C5）的个体通路在牙周炎中的确切作用。在第二项研究中，研究人员进一步提出，研究小组首次发现的新型补体依赖性微生物逃避机制是否会促进牙周细菌的不必要炎症和合作生存。在Aim 3中，那些介导破坏性炎症和/或病原体持久性的途径或成分将被阻断，而那些介导宿主保护作用的途径或成分将保持不变。实验方法涉及炎性牙周炎和宿主-病原体相互作用的临床前小鼠模型。所使用的小鼠要么具有完整的补体系统，要么在定义主要诱导或效应补体途径的关键成分中携带特定突变。转译方法包括使用一组补体特异性治疗抑制剂。已经成功进行安全性试验的补体特异性药物的可用性表明，本项目确定的有希望的干预措施有可能迅速转化为牙周病治疗的临床试验。

DESCRIPTION (provided by applicant): Novel Mechanisms and 'Complement-ary' Therapy in Periodontitis Project Summary Periodontal inflammation affects the majority of adults, while an estimated 10-15% develops severe periodontitis which exerts a systemic impact on the patients (e.g., increased risk for atherosclerosis and diabetes). However, the underlying immunopathology is poorly understood at the molecular level and effective, precisely targeted topical therapeutics are lacking. Clinical and histological observations, as well as experimental studies, suggest involvement of the complement system in periodontitis. However, the precise roles of the various complement pathways in periodontitis have not been defined. Consequently, it is currently uncertain which specific pathways or components need to be blocked to attenuate inflammatory pathology or, alternatively, maintained intact to support host defense. At a first stage, such mechanistic and interventional approaches necessitate the use of appropriate preclinical animal models. The overall objective of this proposal is to bridge the current mechanistic deficit of complement involvement in periodontitis to allow targeted intervention. The proposed project involves a consortium arrangement between the University of Louisville School of Dentistry and the University of Pennsylvania School of Medicine, and brings together leading, complementary, and integrated expertise in the areas of periodontal inflammation, microbial immune evasion, and complement-targeted therapeutics. In Aim 1, a systematic approach is proposed to dissect the precise roles in periodontitis of individual pathways converging to or emanating from central complement hubs (C3, C5) that have already been implicated in preliminary studies. In Aim 2, it is further proposed to investigate whether novel complement-dependent microbial evasion mechanisms, first identified by this group, promote both unwarranted inflammation and the cooperative survival of periodontal bacteria. In Aim 3, those pathways or components that mediate destructive inflammation and/or pathogen persistence will be blocked, whereas those mediating host-protective effects will be kept intact. The experimental approach involves preclinical mouse models of inflammatory periodontitis and host-pathogen interactions. The mice to be used possess either intact complement system or carry specific mutations in key components that define major inductive or effector complement pathways. The translational approach involves the use of a panel of complement-specific therapeutic inhibitors. The availability of complement-specific drugs that have already undergone successful safety trials, indicates that promising interventions identified in this project have potential for rapid translation to clinical trials for periodontal disease treatment.