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Vitamin D and Periodontal Disease

维生素 D 和牙周病

基本信息

批准号：
8733048
负责人：
GILL DIAMOND
金额：
$ 26.25万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-17 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8733048
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 public health relevance receptor binding response transcription factor

项目摘要

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）：口腔上皮的先天免疫是抵抗引起牙周病的病原微生物的第一道防线。作为题为“牙龈细胞中维生素D抗菌活性的诱导”的R21资助的结果，我们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和其他宿主防御介体的表达，导致针对周围病原细菌的抗菌先天免疫防御增加。其他研究表明，维生素D水平与宿主对口腔感染的防御之间存在密切联系。总之，这些数据为我们的总体假设提供了强有力的支持，即维生素D促进牙龈上皮的先天免疫防御。为了解决这一假设，我们提出了一个全面的分析的关系，包括在体外和体内的实验分析，以表征维生素D和先天免疫防御牙周病之间的关系。我们提出两个目标：1。描述维生素D介导的诱导牙龈上皮细胞（GEC）先天免疫的机制。我们将更好地理解的诱导，通过定义响应1，25（OH）2D 3相对于先天免疫基因表达的转录控制和与先天免疫反应途径的相互作用。这将是口腔上皮细胞中与维生素D相关的分子途径的首次表征，以及与先天免疫途径的相互作用。这样做将提供对口腔先天免疫的更好理解。2.在细菌诱导的牙周病小鼠模型中量化维生素D和牙周病之间的关系。我们推测，调节血清维生素D水平直接相关的天然免疫防御能力的牙龈上皮。为了在体内证实这一点，我们将确定维生素D缺乏在基于细菌的牙周病小鼠模型中的作用。由于LL-37的小鼠同源物不受维生素D诱导，我们还将使用在其自身（人，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，以量化增加浓度对先天免疫防御的影响。虽然长期以来一直在研究维生素D在人类健康中的作用，但我们期望从这项研究中获得的结果将代表维生素D对预防慢性感染性疾病（如牙周炎）的贡献的第一个机制分析，并将为维生素D作为治疗剂的开发提供基础。公共卫生相关性：牙周病是由细菌引起的，这些细菌粘附并定植在牙齿附近的牙龈细胞上。我们发表的来自受资助的R21的结果表明，维生素D可以增加牙龈细胞对牙周病相关细菌的免疫防御。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诱导的牙周病。研究结果将支持维生素D作为牙周病和其他口腔感染的治疗方法的发展。