Topical Vitamin D and Periodontal Disease

外用维生素 D 与牙周病

• 批准号: 10382267
• 负责人: GILL DIAMOND
• 金额: $ 54.2万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-02 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10382267
• 关键词: 3-Dimensional; Actinobacillus actinomycetemcomitans; Address; Affect; Anti-Bacterial Agents; Apical; Bacteria; Bioinformatics; Bone Development; Bone Resorption; Calcium; Cells; Cholecalciferol; Chronic; Clinical; Clinical Trials; Complex; Conflict (Psychology); Data; Development; Epigenetic Process; Epithelial; Epithelial Cells; Feedback; Genes; Genetic; Gingiva; Growth; Health; Health Status; Homeostasis; Host Defense; Human; Immune; Immunity; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Kinetics; Lead; Link; Mechanics; Mediating; Mixed Function Oxygenases; Molecular; Mus; Natural Immunity; Operative Surgical Procedures; Oral; Oral cavity; Outcome; Pathway interactions; Peptides; Periodontal Diseases; Periodontitis; Population; Porphyromonas gingivalis; Preventive therapy; Production; Publishing; Regulation; Reporting; Role; Signal Pathway; Surface; Tissues; Tooth Loss; Topical application; Toxic effect; Vitamin D; Vitamin D Deficiency; Vitamin D supplementation; Vitamin D3 Receptor; Vitamins; absorption; antimicrobial; bone loss; commensal microbes; cytokine; cytotoxicity; dysbiosis; mouse model; oral cavity epithelium; oral infection; oral microbial community; oral microbiome; oral supplementation; pathogenic bacteria; periodontopathogen; prevent; response; supervitaminosis; three dimensional cell culture; transcription factor

PROJECT SUMMARY/ABSTRACT Periodontal disease is associated with an increase in Porphyromonas gingivalis, dysbiosis of the commensal microbiota in the subgingival crevice, and chronic inflammation resulting in bone resorption, and ultimately tooth loss. Vitamin D is best known as a principal factor that maintains calcium homeostasis and is required for bone development and homeostasis. However, it is becoming clear that vitamin D has profound actions in immunity and inflammation as well. Both the chronic and aggressive forms of periodontal disease have been associated with vitamin D deficiency in numerous populations. Our recently published data show that the active form of vitamin D, 1,25(OH)2D3, promotes anti-bacterial activity against P. gingivalis by gingival epithelial cells (GEC), and inhibits pro-inflammatory cytokine expression. Experimental vitamin D deficiency in mice leads to gingival inflammation and bone loss. However, clinical trials examining the effect of oral vitamin D supplementation on periodontal disease have led to conflicting results, likely due to natural feedback mechanisms. We therefore hypothesized that topical administration of vitamin D to the gingiva could circumvent this problem. Our preliminary results indicate that when inactive vitamin D is delivered directly to the surface of the gingival epithelium, both in vitro and in mice, we observe a rapid induction of vitamin D-mediated genes, as well as an inhibition of pro-inflammatory cytokines, without cytotoxicity. We also observed that the epithelial cells convert inactive vitamin D3 to both the inactive intermediate (25OHD3), and to active 1,25(OH)2D3 through epithelial cell- expressed hydroxylases, and that this conversion resulted in increased production of the host defense peptide, LL-37. Thus, our overarching hypothesis is that that the gingival epithelium maintains its own intrinsic regulation of vitamin D status, and that topical delivery of vitamin D to the oral epithelium allows direct introduction of high concentrations of active vitamin D to the tissue. This delivery can lead to regulation of vitamin D-regulated genes that can downregulate inflammation and prevent the growth of periopathogenic bacteria, and the resulting bone loss. To address this, we propose the following specific aims: 1) Quantify the relationship between vitamin D and periodontal disease in a mouse model. 2) Define the shifts in the oral microbiome regulated by vitamin D. 3) Characterize the mechanism of vitamin D-mediated induction of innate immunity in cultured human GEC. Together, these aims will support our hypothesis that vitamin D is essential for periodontal health, will help define the mechanism by which this occurs, and will provide a proof of principle that topical administration of vitamin D in the oral cavity can maintain this health status. Vitamin D’s actions are complex and multifaceted, but harnessing its beneficial activities has the potential to change periodontal practice replacing expensive mechanical and surgical procedures with well-reasoned, safe and reliable topical treatments with no toxicity.

项目概要/摘要 牙周病与牙龈卟啉单胞菌的增加、共生菌的失调有关 龈下缝隙中的微生物群，以及导致骨吸收的慢性炎症，最终影响牙齿 损失。维生素 D 是众所周知的维持钙稳态的主要因素，并且是骨骼生长所必需的 发育和稳态。然而，人们越来越清楚维生素 D 在免疫方面具有深远的作用 还有炎症。慢性和侵袭性牙周病都与此相关 许多人群缺乏维生素 D。我们最近发布的数据表明，活性形式 维生素 D，1,25(OH)2D3，促进牙龈上皮细胞 (GEC) 对牙龈卟啉单胞菌的抗菌活性， 并抑制促炎细胞因子的表达。小鼠实验性维生素 D 缺乏导致牙龈萎缩 炎症和骨质流失。然而，临床试验检验了口服维生素 D 补充剂对健康的影响。 牙周病导致了相互矛盾的结果，这可能是由于自然反馈机制造成的。我们因此 假设在牙龈上局部施用维生素 D 可以避免这个问题。我们的 初步结果表明，当无活性的维生素 D 直接输送到牙龈表面时， 在体外和小鼠的上皮细胞中，我们观察到维生素 D 介导的基因的快速诱导，以及 抑制促炎细胞因子，无细胞毒性。我们还观察到上皮细胞转化为 无活性维生素 D3 转化为无活性中间体 (25OHD3)，并通过上皮细胞转化为活性 1,25(OH)2D3- 表达羟化酶，并且这种转化导致宿主防御肽的产量增加， LL-37。因此，我们的首要假设是牙龈上皮维持其自身的内在调节 维生素 D 状态的变化，并且将维生素 D 局部递送至口腔上皮可以直接引入高 组织中活性维生素 D 的浓度。这种传递可以导致维生素 D 调节基因的调节 可以下调炎症并防止周围病原细菌的生长，以及由此产生的骨骼 损失。为了解决这个问题，我们提出以下具体目标：1) 量化维生素 D 之间的关系 和小鼠模型中的牙周病。 2) 定义口腔微生物组的变化 3) 表征培养物中维生素 D 介导的先天免疫诱导机制 人类 GEC。总之，这些目标将支持我们的假设，即维生素 D 对牙周健康至关重要， 将有助于定义发生这种情况的机制，并将提供主题证明 在口腔中施用维生素D可以维持这种健康状态。维生素D的作用很复杂 多方面的，但利用其有益活动有可能改变牙周实践，取代 昂贵的机械和外科手术以及合理、安全和可靠的局部治疗，无需 毒性。