Mechanisms of Resolvin E1 in Periodontal Regeneration

 描述(由申请人提供)：控制牙周再生中的炎症是一个主要的公共卫生问题。美国大约50%的人口患有某种形式的牙周病，组织工程手术不能完全恢复硬组织和软组织。控制内源性炎症是组织工程成功的绝对要求。在再生过程中迫切需要新的治疗方法来控制局部炎症。这项R01提案的长期目标是利用炎症的自然分解来控制局部炎症并加速再生。分解素介导炎症的消退，促进牙周再生和恢复动态平衡。我们小组提出了一个新的概念，即炎症性疾病可能是由于主动解决失败而导致的。越来越多的证据表明，内源性分解程序的激动剂可能是控制牙周再生和重建中炎症的最佳方法。中心假设是炎症途径和介质的消解可以被利用来控制牙周组织中的炎症，从而使牙周组织能够再生和重建。我们已经证明，脂氧素和分解素的输送通过控制炎症极大地促进了组织再生。溶血素的作用也超出了中性粒细胞的控制，包括受体介导的破骨细胞和成骨细胞在伤口愈合和骨再生中的作用。我们将利用特定的RvE1受体敲除(KO)和受体过表达的转基因小鼠来确定RvE1诱导骨形成的关键内源控制机制，通过阐明促进成骨细胞介导的骨形成和限制破骨细胞活性的信号合成途径来确定骨细胞对RvE1的反应基础，并通过检测RvE1诱导的促炎和抗炎脂质介质的分布来揭示脂介质协同作用的复杂性和异种特异性分解激动剂的特征。这些研究的结果将促进我们对组织再生中炎症的自然消解机制的了解，以开发以生物工程为基础的新的针对牙周再生的策略。我们经验丰富的研究团队由细胞生物学、药物生物化学、动物模型和牙周再生方面的专家组成，这些专家都很有能力开展这一项目。

 DESCRIPTION (provided by applicant): Control of inflammation in periodontal regeneration is a major public health problem. Approximately 50% of the population of the United States has some form of periodontal disease and tissue engineering procedures cannot completely restore hard and soft tissues. Control of endogenous inflammation is an absolute requirement for tissue engineering success. There is a critical need for new therapeutics in regeneration that control local inflammation. The long-term goal of this R01 proposal is to utilize natural resolution of inflammation to control local inflammation and accelerate regeneration. Resolvins mediate resolution of inflammation facilitating periodontal regeneration and a return to homeostasis. Our group introduced the novel concept that inflammatory disease may result from a failure of active resolution. Accumulating evidence suggests that agonists of endogenous resolution programs may be the best approach to control inflammation in periodontal regeneration and reconstruction. The Central Hypothesis is that resolution of inflammation pathways and mediators can be harnessed to control inflammation in periodontal tissues enabling regeneration and reconstruction. We have demonstrated that delivery of lipoxins and resolvins greatly enhances tissue regeneration by control of inflammation. Resolvins also have actions beyond control of neutrophils including receptor mediated control of osteoclast and osteoblast function in wound healing and bone regeneration. We will identify key endogenous control mechanisms for bone formation induced by RvE1 using specific RvE1 receptor knock-out (KO) and receptor over-expressing transgenic mice, determine the basis for bone cell responses to RvE1 by elucidation of signal anabolic pathways that promote osteoblast mediated bone formation and limit osteoclast activity, and unravel the complexities of lipid mediator synergy and characterize hetero- specific resolution agonist amplification by determining pro and anti-inflammatory lipid mediator profiles induced by RvE1. Results from these studies will advance our knowledge of mechanisms in natural resolution of inflammation in tissue regeneration to develop novel bioengineering-based strategies targeted for periodontal regeneration. Our experienced research team consists of experts in cell biology, pharmacological biochemistry, animal models and periodontal regeneration that are well positioned to carry out this project.