Vitamin D and Periodontal Disease

维生素 D 和牙周病

• 批准号: 8401686
• 负责人: GILL DIAMOND
• 金额: $ 18.36万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ DENTAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-17 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8401686
• 关键词: Address; Affect; Anti-Bacterial Agents; Bacteria; CAP18 lipopolysaccharide-binding protein; CD14 gene; Cells; Cholecalciferol; Chronic; Communicable Diseases; Data; Databases; Development; Enzyme Gene; Epithelial Cells; Epithelium; Exhibits; Funding; Gene Expression; Genetic Polymorphism; Gingiva; Gingivitis; Grant; Health; Hereditary Disease; Homologous Gene; Hormones; Host Defense; Human; Immune; Immune response; Immunologic Receptors; In Vitro; Infection; Kinetics; Lead; Mediating; Mediator of activation protein; Microbe; Molecular; Mus; Natural Immunity; Oral; Oral cavity; Pathway interactions; Pattern; Periodontal Diseases; Periodontitis; Play; Prevention; Preventive; Publishing; Receptor Gene; Relative (related person); Research; Response Elements; Role; Serum; Therapeutic Agents; Tooth structure; Transcriptional Regulation; Vitamin D; Vitamin D3 Receptor; antimicrobial peptide LL-37; base; bone loss; in vivo; in vivo Model; microorganism; mouse model; oral cavity epithelium; oral infection; oral microbiome; prevent; promoter; receptor binding; response; transcription factor

DESCRIPTION (provided by applicant): Innate immunity in the oral epithelium represents the first line of defense against the pathogenic microorganisms that cause periodontal disease. As a result of an R21 grant, entitled "Vitamin D induction of antibacterial activity in gingival cells" e have recently shown that oral epithelial cells are capable of converting inactive vitamin D to the active form (1,25(OH)2 Vitamin D3), and that this hormone induces the expression of an antimicrobial peptide, LL-37, and other host defense mediators, resulting in an increase in the antibacterial innate immune defense against periopathogenic bacteria. Other studies have demonstrated a strong association between vitamin D levels and the host defense against infection in the oral cavity. Together the data provide strong support to our overarching hypothesis that vitamin D promotes innate immune defense in the gingival epithelium. To address this hypothesis, we propose a comprehensive analysis of the relationship, including both in vitro and in vivo experimental analyses to characterize the relationship between vitamin D and the innate immune defense in periodontal disease. We propose two aims: 1. Characterize the mechanism of vitamin D-mediated induction of innate immunity in gingival epithelial cells (GEC). We will better understand the induction by defining the response to 1,25(OH)2D3 with respect to transcriptional control of innate immune gene expression and the interaction with the innate immune response pathways. This will be the first characterization of the molecular pathways associated with vitamin D in oral epithelial cells, and of the cross-talk with innate immune pathways. Doing so will provide a greater understanding of innate immunity in the oral cavity. 2. Quantify the relationship between vitamin D and periodontal disease in a mouse model of bacteria-induced periodontal disease. We hypothesize that regulating serum vitamin D levels directly correlates with innate immune defense capability in the gingival epithelium. To confirm this in vivo, we will determine the effect of vitamin D depletion in a bacteria-based mouse model of periodontal disease. Since the mouse homologue to LL-37 is not induced by vitamin D, we will also use a humanized strain that expresses LL-37 under the control of its own (human, vitamin D-regulated) promoter. We will also supplement both local and systemic vitamin D levels to quantify the effect of increased concentrations on the innate immune defenses. While long examined for its role in human health, the results we expect to obtain from this study would represent the first mechanistic analysis of the contribution of vitamin D to defense against a chronic infectious disease such as periodontitis, and will provide the basis for the development of vitamin D as a therapeutic agent. PUBLIC HEALTH RELEVANCE: Periodontal disease is caused by bacteria that adhere to and colonize the gingival cells adjacent to the teeth. Our published results from a funded R21 demonstrated that vitamin D can increase the immune defenses of gingival cells against the bacteria associated with periodontal disease. Here we propose to study the mechanism by which this occurs, and to determine whether we can prevent bacteria-induced periodontal disease in a mouse model. The results will support the development of vitamin D as a therapy for periodontal disease and other oral infections.

描述（由申请人提供）：口腔上皮细胞的先天免疫是针对引起牙周病的病原微生物的第一道防线。作为题为“维生素 D 诱导牙龈细胞抗菌活性”的 R21 资助的结果，最近表明口腔上皮细胞能够将非活性维生素 D 转化为活性形式（1,25(OH)2 维生素 D3） ，并且这种激素诱导抗菌肽 LL-37 和其他宿主防御介质的表达，从而增强针对周围病原细菌的抗菌先天免疫防御。其他研究表明，维生素 D 水平与宿主抵抗口腔感染的防御能力之间存在密切关系。这些数据共同有力地支持了我们的总体假设，即维生素 D 可以促进牙龈上皮的先天免疫防御。为了解决这一假设，我们提出了对这种关系的全面分析，包括体外和体内实验分析，以表征维生素 D 与牙周病中先天免疫防御之间的关系。我们提出两个目标： 1. 描述维生素 D 介导的牙龈上皮细胞 (GEC) 天然免疫诱导机制。通过定义 1,25(OH)2D3 对先天免疫基因表达的转录控制以及与先天免疫反应途径相互作用的反应，我们将更好地理解诱导。这将是口腔上皮细胞中与维生素 D 相关的分子途径以及与先天免疫途径相互作用的首次表征。这样做将有助于更好地了解口腔的先天免疫。 2. 在细菌诱发的牙周病小鼠模型中量化维生素 D 与牙周病之间的关系。我们假设调节血清维生素 D 水平与牙龈上皮的先天免疫防御能力直接相关。为了在体内证实这一点，我们将在基于细菌的牙周病小鼠模型中确定维生素 D 消耗的影响。由于 LL-37 的小鼠同源物不是由维生素 D 诱导的，因此我们还将使用在其自身（人类、维生素 D 调节的）启动子控制下表达 LL-37 的人源化菌株。我们还将补充局部和全身维生素 D 水平，以量化浓度增加对先天免疫防御的影响。虽然人们对维生素 D 在人类健康中的作用进行了长期研究，但我们期望从这项研究中获得的结果将首次对维生素 D 对防御牙周炎等慢性传染病的作用进行机制分析，并将为开发维生素 D 提供基础。维生素D作为治疗剂。 公共卫生相关性：牙周病是由粘附并定植于牙齿附近牙龈细胞的细菌引起的。我们发表的 R21 资助结果表明，维生素 D 可以增强牙龈细胞对牙周病相关细菌的免疫防御能力。在这里，我们建议研究这种情况发生的机制，并确定我们是否可以在小鼠模型中预防细菌引起的牙周病。研究结果将支持维生素 D 的开发，用于治疗牙周病和其他口腔感染。