Mechanisms of Pro-Resolving Mediators in Periodontal Regeneration

牙周再生中促溶解介质的机制

• 批准号: 10674528
• 负责人: THOMAS Elliott VAN DYKE
• 金额: $ 46.31万
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674528
• 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; Goals; Host Defense Mechanism; Human; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Knowledge; LOX gene; Lipoxins; Macrophage; Mediating; Mediator; Mesenchymal Stem Cells; Metabolism; Molecular Target; National Institute of Dental and Craniofacial Research; Natural regeneration; Organ; Pathway interactions; Periodontal Ligament; Periodontitis; Phenotype; Production; Proliferating; Property; Publishing; Research; Resolution; Signal Pathway; Signal Transduction; Strategic Planning; Testing; Tissue Engineering; Tissues; Transplantation; analog; bone; bone healing; craniofacial tissue; design; enzyme biosynthesis; experimental study; healing; human disease; immunoregulation; improved; injured; lipid biosynthesis; lipid mediator; lipoxin A4; lipoxin B4; 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 niche; 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.

项目总结