Mechanisms of Pro-Resolving Mediators in Periodontal Regeneration

牙周再生中促溶解介质的机制

• 批准号: 10439454
• 负责人: THOMAS Elliott VAN DYKE
• 金额: $ 45.85万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439454
• 关键词: Address; Animal Model; Animals; Anti-Inflammatory Agents; Arachidonate 15-Lipoxygenase; Attenuated; Biochemical Process; Biochemistry; Biomimetics; Bone Regeneration; CD59 Antigen; Cicatrix; Clinical; Connective Tissue; Dental; Dental Cementum; Developmental Biology; Diet; Disease; Dose; Environment; Family suidae; Fibrosis; Generations; Goals; Host Defense Mechanism; Human; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Knowledge; LOX gene; Lipoxins; Mediating; Mediator of activation protein; Mesenchymal Stem Cells; Metabolism; Molecular Target; National Institute of Dental and Craniofacial Research; Natural regeneration; Organ; Pathway interactions; Periodontal Ligament; Periodontitis; Phenotype; Production; Property; Publishing; Research; Resolution; Signal Pathway; Signal Transduction; Strategic Planning; Testing; Tissue Engineering; Tissues; Transplantation; analog; base; bone; bone healing; craniofacial tissue; enzyme biosynthesis; experimental study; healing; human disease; immunoregulation; improved; injured; lipid mediator; lipoxin A4; lipoxin B4; macrophage; man; microbiome; nanoparticle; novel; oral tissue; preclinical study; programs; receptor expression; reconstruction; regeneration model; regenerative; response; stem cell biology; stem cell differentiation; stem cell function; stem cell proliferation; stem cell therapy; stem cells; synthetic enzyme; therapeutic evaluation; tissue injury; tissue regeneration; translation to humans; translational approach; wound healing

Project Summary Uncontrolled inflammation is a major impediment to tissue engineering, regeneration and reconstruction of both diseased and injured tissues resulting in further tissue injury, tissue scarring and fibrosis. Stem cell activity is disrupted by persistent signals promoting inflammation, whereas specific anti-inflammatory signals enhance stem cell activity. In successful regeneration, mesenchymal stem cells assume an anti-inflammatory phenotype. Specialized Proresolving lipid Mediators (SPMS), including Lipoxin A4 (LXA4), attenuate the dental stem cell inflammatory response. Resolution of inflammation is an active biochemical and metabolic process, not merely a passive termination of inflammation, mediated by SPMs. SPMs activate wound healing with tissue regeneration instead of fibrosis and scarring and directly improve bone healing and regeneration, including in periodontitis. Human periodontal ligament stem cells release SPMs, including lipoxin, to regulate immunomodulatory and pro-healing properties. Characterizing the biomimetic properties of SPMs in humans is hampered by a lack of suitable large animal models. There is a critical need for a validated large animal regeneration model to test therapeutic potential of SPMs for translation to humans. Our goal is to determine the pathways to regeneration that control local inflammation and enhance mesenchymal stem cell differentiation into connective tissues, including bone. The Central Hypothesis is that resolution of inflammation pathways and mediators can promote regeneration of the periodontal organ (bone, cementum and periodontal ligament) by directing stem cell phenotype, proliferation and differentiation. In this application, we will use a large animal model to dissect the SPM pathways leading to periodontal ligament stem cell control of regeneration. In this proposal, we will: 1: Provide direct evidence for SPM production by Yorkshire miniature pig periodontal ligament stem cells (mpPDLSC) by determining the lipid mediator profile of mpPDLSC; 2: Determine stem cell function in miniature pig by determining mpPDLSC proliferation and response to SPMs, and determination of synthetic enzyme expression, signaling pathways and SPM receptor expression, and 3: Demonstrate SPM enhanced stem cell mediated periodontal regeneration in Miniature Pigs using SPM local delivery to enhance periodontal regeneration alone or in combination with transplanted, ex vivo expanded miniature pig stem cells. Results from these studies will advance our practical clinical knowledge of dose and delivery of lipoxins in tissue regeneration, identify potential new molecular targets, and further develop and characterize a large animal model to test novel stem cell-based strategies for translation to human oral and craniofacial tissue regeneration. The research team comprises experts in periodontal regeneration, biochemistry, and large animal models.

项目概要 不受控制的炎症是组织工程、再生和重建的主要障碍 患病和受伤的组织导致进一步的组织损伤、组织疤痕和纤维化。干细胞 活性被促进炎症的持续信号破坏，而特定的抗炎信号 增强干细胞活性。在成功再生过程中，间充质干细胞具有抗炎作用 表型。专门的溶解脂质介质 (SPMS)，包括脂氧素 A4 (LXA4)，可减弱牙齿损伤 干细胞炎症反应。炎症的消退是一个活跃的生化和代谢过程， 不仅仅是由 SPM 介导的炎症的被动终止。 SPM 可以促进伤口愈合 组织再生而不是纤维化和疤痕，直接改善骨骼愈合和再生， 包括牙周炎。人牙周膜干细胞释放 SPM，包括脂氧素，以调节 免疫调节和促愈合特性。表征 SPM 在人体中的仿生特性 由于缺乏合适的大型动物模型而受到阻碍。迫切需要经过验证的大型动物 再生模型来测试 SPM 转化为人类的治疗潜力。我们的目标是确定 控制局部炎症和增强间充质干细胞的再生途径 分化为结缔组织，包括骨。中心假设是解决 炎症途径和介质可以促进牙周器官（骨、牙骨质）的再生 和牙周膜）通过指导干细胞表型、增殖和分化。在这个应用程序中， 我们将使用大型动物模型来剖析导致牙周膜干细胞控制的 SPM 途径 的再生。在本提案中，我们将： 1：提供约克郡微型模型生产 SPM 的直接证据 通过测定猪牙周膜干细胞（mpPDLSC）的脂质介质谱； 2： 通过测定 mpPDLSC 增殖和对 SPM 的反应来确定小型猪的干细胞功能， 合成酶表达、信号通路和SPM受体表达的测定，以及3： 使用 SPM 局部演示 SPM 增强小型猪干细胞介导的牙周再生 单独或与移植、离体扩张相结合的递送以增强牙周再生 微型猪干细胞。这些研究的结果将提高我们对剂量和剂量的实用临床知识。 在组织再生中递送脂氧素，识别潜在的新分子靶标，并进一步开发和 表征大型动物模型，以测试基于干细胞的新型策略，以转化为人类口腔和 颅面组织再生。研究团队由牙周再生领域的专家组成， 生物化学和大型动物模型。