Topical Vitamin D and Periodontal Disease

外用维生素 D 与牙周病

• 批准号: 10600091
• 负责人: GILL DIAMOND
• 金额: $ 46.23万
• 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/10600091
• 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; Data; Development; Epigenetic Process; Epithelial Cells; Epithelium; 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; 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; cathelicidin antimicrobial peptide; 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.

项目总结/文摘