Mechanisms of Resolvin E1 in Periodontal Regeneration

Resolvin E1 在牙周再生中的作用机制

• 批准号: 8861681
• 负责人: THOMAS Elliott VAN DYKE
• 金额: $ 49.53万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8861681
• 关键词: Acute; Address; Adult; Agonist; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Biochemistry; Biological Factors; Biomedical Engineering; Bone Regeneration; Cell physiology; Cellular biology; Chronic; Data; Defect; Development; Disease; Failure; Goals; Homeostasis; Immunosuppression; Inflammation; Inflammatory; Knock-out; Knowledge; Lesion; Link; Lipoxins; Literature; Mediating; Mediator of activation protein; Molecular; Mus; Myeloid Cells; National Institute of Dental and Craniofacial Research; Natural regeneration; Operative Surgical Procedures; Oral; Osteoblasts; Osteoclasts; Osteogenesis; Outcome; Pathology; Pathway interactions; Periodontal Diseases; Periodontitis; Population; Positioning Attribute; Postoperative Period; Procedures; Process; Public Health; Publishing; Reporting; Research; Resolution; Role; Serum; Signal Pathway; Signal Transduction; System; Techniques; Tissue Engineering; Tissues; Topical application; Transgenic Mice; United States; Work; Wound Healing; base; bone cell; craniofacial; experience; inhibitor/antagonist; injured; lipid mediator; neutrophil; novel; novel therapeutics; pre-clinical; programs; public health relevance; receptor; reconstruction; regenerative therapy; research study; response; soft tissue; success; tissue reconstruction; tissue regeneration

 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.

 描述（由申请人提供）：牙周再生中的炎症控制是一个主要的公共卫生问题。大约50%的美国人口患有某种形式的牙周病，组织工程程序不能完全恢复硬组织和软组织。内源性炎症的控制是组织工程成功的绝对要求。迫切需要控制局部炎症的再生新疗法。R01提案的长期目标是利用炎症的自然消退来控制局部炎症并加速再生。消退素介导炎症消退，促进牙周再生和恢复体内平衡。我们的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的失败。越来越多的证据表明，内源性解决方案的激动剂可能是最好的方法来控制炎症牙周再生和重建。中心假设是，炎症途径和介质的解决可以用来控制牙周组织的炎症，使再生和重建。我们已经证明，脂氧素和消退素的递送通过控制炎症极大地增强了组织再生。消退蛋白还具有超出嗜中性粒细胞控制的作用，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功能控制。我们将使用特异性RvE1受体敲除（KO）和受体过表达转基因小鼠来确定RvE1诱导骨形成的关键内源性控制机制，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代谢途径来确定骨细胞对RvE1反应的基础，并通过测定RvE1诱导的促炎和抗炎脂质介质谱来阐明脂质介质协同作用的复杂性并表征异源特异性消退激动剂扩增。这些研究的结果将推进我们对组织再生中炎症自然消退机制的认识，以开发针对牙周再生的新的基于生物工程的策略。我们经验丰富的研究团队由细胞生物学、药理生物化学、动物模型和牙周再生方面的专家组成，他们有能力开展该项目。