Novel Lipid Mediators in Periodontal Disease Resolution Circuits

急性炎症在“不受控制”的情况下，如在生物恐怖袭击事件中，可能导致对个人生命的巨大威胁和对公共卫生的不适当风险。人中性粒细胞（PMN）通过释放影响组织完整性和口腔功能的脂质衍生介质（LM）和促炎产物在急性炎症和牙周病（PD）相关组织损伤中发挥关键作用。PI的实验室和正在进行的工作中出现了新的证据，表明缓解期间对PMN的控制是一个积极的过程，在渗出液中发现了由PMN产生的称为消退素（RV）和二十二碳三烯（DT）的有效新型保护性LM，可减少急性炎症和PMN介导的组织损伤。从 通过这些发现，现在很清楚，分辨率的分子图，一个重要的自我平衡过程，在很大程度上仍然是未知的。该多学科专业研究中心的子项目0001的重点是使用脂质组学结合蛋白质组学系统地阐明新的前分辨电路。子项目0001将检验LM（包括RV、DT及其阿司匹林触发的差向异构体）调节内源性抗炎回路（控制白细胞运输和解决所需的关键分子事件）的假设。微生物产品和口腔外科实践中广泛使用的治疗（局部麻醉剂，NSAID）破坏这些新的分辨率电路会导致组织炎症。为了验证这一点，提出了3个具体目标：目标1将建立LM和分子的形成和作用， 通过Core 9002将识别出的缓解组分转化为人类的指令，与PD相比，小鼠腹膜炎的缓解回路。目的2中的实验设计为使用基因工程小鼠鉴定参与PD消退的LM受体，以及用人PMN和重组受体两者标记的RV和DT。目标3将确定微生物产品，当前抗炎药和局部镇痛药的影响，以及时解决问题。广泛的长期目标有两个方面：1）阐明PD中微生物防御和PMN介导的组织损伤期间诱发的口腔分辨率和相关基因的人类图谱，以及2）为口腔外科医生和牙医提供分辨率的分子坐标图谱，以改善当前的治疗实践和生物恐怖袭击的准备。

Acute inflammation when "uncontrolled" can lead, as in the event of bioterrorist attacks, to massive threat to individual life and undue risk to public health. Human neutrophils (PMN) play pivotal roles in acute inflammation and periodontal disease (PD)-associated tissue injury by releasing lipid-derived mediators (LM) and pro-inflammatory products that affect both tissue integrity and oral function. New evidence has emerged from the PI's laboratory and work in progress indicating that control of PMN during resolution is an active process with the identification in exudates of potent novel protective LM termed resolvins (RV) and docosatrienes (DT) generated by PMN that reduce acute inflammation and PMN-mediated tissue injury. From these findings, it is now clear that the molecular map of resolution, an important homeostatic process, remains largely uncharted. The focus of sub-project 0001 in this multi-disciplinary Specialized Center for Research is on systematic elucidation of novel pro-resolving circuits using lipidomics coupled with proteomics. Sub-Project 0001 will test the hypothesis that LM, including RV, DT, and their aspirin-triggered epimers, regulate endogenous anti-inflammatory circuits that govern leukocyte traffic and key molecular events required for resolution. Disruption of these novel resolution circuits by microbial products and widely used treatments in oral surgical practices (local anesthetics, NSAIDs) prolongs tissue inflammation. To test this, 3 specific aims are proposed: Aim 1 will establish the formation and role of LM and molecular circuitry of resolution in murine peritonitis compared to PD with the directive of translating identified resolution components to humans via Core 9002. Experiments in Aim 2 are designed to identify the LM receptors involved in resolution of PD using genetically engineered mice, and labeled-RV and DT with both human PMN and recombinant receptors. Aim 3 will determine the impact of microbe products, current anti-inflammatories, and local analgesics in timely resolution. The broad long-term goals are two-fold: 1) elucidate the human map of oral resolution and associated genes evoked during microbial defense and PMN-mediated tissue injury in PD, and 2)provide map(s) with molecular coordinates of resolution to oral surgeons and dentists to improve current treatment practices and preparedness for bioterrorist attacks.