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.

项目摘要/摘要 牙周疾病与牙龈卟啉单胞菌的增加有关，共生的营养不良 subingival缝隙中的微生物群和慢性炎症导致骨骼分辨率，最终也是 损失。维生素D是维持钙稳态的主要因素，骨骼需要 发展和体内平衡。但是，很明显，维生素D在免疫方面具有深刻的作用 和炎症。牙周疾病的慢性和侵略性形式都已经相关 众多人群中的维生素D缺乏症。我们最近发布的数据表明， 维生素D，1,25（OH）2d3，通过牙龈上皮细胞（GEC），，促进针对牙龈疟原虫的抗细菌活性（GEC）， 并抑制促炎性细胞因子的表达。小鼠的实验性维生素D缺乏导致牙龈 炎症和骨质流失。但是，检查补充口服维生素D对的临床试验对 牙周疾病导致了矛盾的结果，这可能是由于自然反馈机制所致。因此，我们 假设局部维生素D对牙龈的局部施用可以避免此问题。我们的 初步结果表明，当不活跃的维生素D直接传递到牙龈表面时 在体外和小鼠中，我们都观察到维生素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换 非活性维生素D3均至非活性中间体（25OHD3），以及通过上皮细胞的活性1,25（OH）2d3 表达的羟化酶，这种转化导致宿主防御肽的产生增加， LL-37。这就是我们的总体假设是，牙龈上皮保持其自身的内在调节 维生素D状态，以及将维生素D递送到口服上皮的局部递送允许直接引入高 活性维生素D的浓度到组织。这种递送可以导致维生素D调节基因的调节 这可以下调炎症并防止邻接细菌的生长，并产生的骨骼 损失。为了解决这个问题，我们提出以下具体目的：1）量化维生素D之间的关系 和小鼠模型中的牙周疾病。 2）定义口服微生物组的移位 维生素D。3）表征维生素D介导的先天免疫诱导的机制 人类Gec。这些目标共同支持我们的假设，即维生素D对于牙周健康至关重要， 将有助于定义发生这种情况的机制，并提供原则证明 口腔中维生素D的给药可以维持这种健康状况。维生素D的作用很复杂， 多方面的，但利用其有益的活动有可能改变牙周练习。 昂贵的机械和外科手术，具有良好的，安全和可靠的局部处理，没有 毒性。