Mechanisms of Pro-Resolving Mediators in Periodontal Regeneration

牙周再生中促溶解介质的机制

• 批准号: 10764989
• 负责人: Fernando Guastaldi
• 金额: $ 21.67万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10764989
• 关键词: Acids; Address; Anabolism; Animal Experiments; Animal Model; Arachidonate 12-Lipoxygenase; Arachidonate 15-Lipoxygenase; Arachidonate 5-Lipoxygenase; Binding; Biological Assay; Biological Availability; Blood; CMKLR1 gene; Clinical; Clinical Trials; Data; Dental Cementum; Diet; Dietary Supplementation; Disease; Disease Outcome; Docosahexaenoic Acids; Docosahexaenoic acid supplement; Eicosapentaenoic Acid; Enzyme-Linked Immunosorbent Assay; Experimental Animal Model; Family suidae; Functional disorder; Future; GPR18 receptor; GPR32 gene; Gingival Indexes; Hemorrhage; Histology; Hydroxylation; Immune response; Immunohistochemistry; Inflammation; Inflammatory; Intake; Kidney; Knowledge; Leukotriene Production; Lipoxygenase; Literature; Liver; Mass Spectrum Analysis; Measures; Mediator; Messenger RNA; Metabolic Pathway; Monitor; N-3 polyunsaturated fatty acid; Natural regeneration; Omega-3 Fatty Acids; Organ; Osteoblasts; Osteoclasts; Outcome; Pathway interactions; Periodontal Diseases; Periodontal Ligament; Periodontitis; Phenotype; Polyunsaturated Fatty Acids; Population; Prevention; Procedures; Production; Proliferating; Proteins; Publishing; Receptor Cell; Regenerative research; Research; Resolution; Series; Spleen; TNFSF11 gene; Testing; Tissues; Toxic effect; Transplantation; Treatment outcome; bone; bone metabolism; clinical outcome measures; dietary supplements; experimental study; human disease; immunogenicity; improved; lipid mediator; microCT; microbiome; peripheral blood; pharmacologic; porcine model; preclinical study; protein activation; receptor; receptor expression; receptor function; response; stem cell model; stem cells; tissue regeneration; wound healing

Dietary supplementation with the n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for improving prevention or outcomes of inflammatory diseases, including periodontitis, has been suggested and supported in the literature. However, there remains a critical need to characterize their mechanism of action to optimize the use of nutritional supplements to benefit the population. There are major gaps in knowledge as it pertains to the mechanisms by which EPA and DHA exert their functional effects. Mechanistically, EPA and DHA supplements in the diet increase the concentration of downstream hydroxylated-EPAs (HEPEs) including 18-HEPE, and hydroxylated-DHAs including 17-HDHA, which are bioactive compounds. 18-HEPE and 17-HDHA are also the precursors for the immunoresolvents known as E-series and D-series resolvins, respectively, which improve periodontal disease outcomes through the activation of specific receptors on stem cells. There remain major gaps in our understanding of the mechanistic relationship between stem cell dysfunction and periodontitis. Our data lead us to the hypothesis that dietary supplementation with EPA and DHA, or their HEPE/HDHA metabolites, will have an impact on treatment outcomes for periodontitis, in part, through the activation of the resolvin/stem cell receptor axis. We will test the hypothesis using a combination of EPA/DHA- and HEPE/HDHA- based dietary supplements in our pig model of stem cell enhanced periodontal regeneration measuring clinical outcomes and investigating mechanism using cutting-edge mass spectrometry-based approaches and assessments of SPM receptor expression and function. Overall, the proposed research will provide much needed clarity to the field of n-3 PUFAs and periodontal disease. The data will specifically provide a scientific rationale for future precision clinical trials with dietary supplements for periodontitis treatment and prevention. The Central Hypothesis is that dietary supplements containing EPA/DHA or HEPE/HDHA precursors of resolvins will enhance resolution of inflammation pathways and mediator production to promote regeneration of the periodontal organ (bone, cementum, and periodontal ligament) by directing stem cell phenotype, proliferation, and differentiation. In this supplement, we will use our ongoing large-animal model experiments to dissect the impact of dietary supplements on the SPM pathways leading to periodontal ligament stem cell control of regeneration. In the miniature pig periodontal regeneration experiments, we will determine whether dietary supplementation with EPA/DHA or concentrated HEPE/HDHA resolvin precursors enhances periodontal regeneration alone or in combination with transplanted, ex vivo expanded miniature pig stem cells and determine the impact of dietary supplementation with EPA/DHA or concentrated HEPE/HDHA resolvin precursors on systemic (blood) and local tissue levels of pro-inflammatory and proresolving lipid mediators. These experiments are critical and focused to determine the potential of dietary supplementation with n-3 PUFAs for periodontal regeneration.

膳食补充n-3多不饱和脂肪酸（PUFA）、二十碳五烯酸（EPA）和 二十二碳六烯酸（DHA）用于改善炎性疾病的预防或结果，包括 牙周炎，已提出并支持在文献中。然而，仍然迫切需要 描述其作用机制，以优化营养补充剂的使用， 人口关于EPA和DHA发挥作用的机制， 其功能效果。从机制上讲，饮食中的EPA和DHA补充剂增加了 下游羟基化EPA（HEPE），包括18-HEPE，和羟基化DHA，包括17-HDHA， 它们是生物活性化合物。18-HEPE和17-HDHA也是免疫溶剂的前体 分别称为E-系列和D-系列消退素，其通过以下方式改善牙周疾病的结果： 激活干细胞上的特定受体。在我们对世界和平的理解方面， 干细胞功能障碍与牙周炎的机制关系我们的数据让我们假设 膳食补充EPA和DHA或其HEPE/HDHA代谢物， 牙周炎的治疗结果，部分是通过激活消退素/干细胞受体轴。我们 我们将使用EPA/DHA和HEPE/HDHA为基础的膳食补充剂组合来测试这一假设， 干细胞促进牙周组织再生的猪模型的临床结果测量和研究 使用尖端的基于质谱的方法和SPM受体评估的机制 表达和功能。总的来说，拟议的研究将为n-3领域提供急需的清晰度。 PUFAs与牙周病这些数据将为未来的精确度提供科学依据 牙周炎治疗和预防的膳食补充剂的临床试验。中心假设是 含有消退素的EPA/DHA或HEPE/HDHA前体的膳食补充剂将提高消退 炎症途径和介体产生以促进牙周器官（骨， 牙骨质和牙周韧带）通过指导干细胞表型、增殖和分化。在这 补充，我们将使用我们正在进行的大型动物模型实验来剖析饮食的影响， 补充SPM途径导致牙周膜干细胞控制再生。在 小型猪牙周再生实验，我们将确定是否饮食补充， EPA/DHA或浓缩的HEPE/HDHA消退素前体单独或联合增强牙周再生 与移植的、离体扩增的小型猪干细胞组合，并确定饮食对小型猪干细胞的影响。 补充EPA/DHA或浓缩的HEPE/HDHA消退素前体对全身（血液）和 促炎和促分解脂质介质的局部组织水平。这些实验至关重要， 重点是确定饮食补充n-3 PUFA用于牙周再生的潜力。

项目成果

Resolvin D1 modulates periodontal ligament fibroblast function.

Resolvin D1 调节牙周膜成纤维细胞功能。

• DOI: 10.1002/jper.22-0462
• 发表时间: 2023
• 期刊: Journal of periodontology
• 影响因子: 4.3
• 作者: Zarrough,AhmedE;Hasturk,Hatice;Stephens,DanielleN;VanDyke,ThomasE;Kantarci,Alpdogan
• 通讯作者: Kantarci,Alpdogan

Transcriptomics of type 2 diabetic and healthy human neutrophils.

• DOI: 10.1186/s12865-021-00428-6
• 发表时间: 2021-06-16
• 期刊: BMC immunology
• 影响因子: 3
• 作者: Kleinstein SE;McCorrison J;Ahmed A;Hasturk H;Van Dyke TE;Freire M
• 通讯作者: Freire M

Pro-resolving mediators in the regulation of periodontal disease.

• DOI: 10.1016/j.mam.2017.04.006
• 发表时间: 2017-12
• 期刊: Molecular aspects of medicine
• 影响因子: 10.6
• 作者: Van Dyke TE

Immunomodulation of periodontitis with SPMs.

• DOI: 10.3389/froh.2023.1288722
• 发表时间: 2023
• 期刊: FRONTIERS IN ORAL HEALTH
• 作者: Sahni, Vaibhav;Van Dyke, Thomas E
• 通讯作者: Van Dyke, Thomas E

Periodontitis: a host mediated disruption of microbial homeostasis.

• DOI: 10.1007/s40496-020-00256-4
• 发表时间: 2020-03
• 期刊: Current oral health reports
• 作者: Yu N;Van Dyke TE
• 通讯作者: Van Dyke TE