Vitamin D and Periodontal Disease

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R21资助的结果，题为“牙龈细胞中抗菌活性的维生素D诱导”，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和其他宿主防御介质的表达，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，以及流行病学研究，以表征维生素D和先天免疫防御牙周病之间的关系。我们提出三个目标：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。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。3.确定人类血清维生素D水平与牙周病之间的关系。我们假设维生素D可以通过调节先天免疫防御来影响人类牙周病的发病和严重程度。我们将量化牙周病的严重程度和血清维生素D水平之间的相关性。这些水平也将与龈下微生物群的变化相关。虽然长期研究其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在慢性感染性疾病（如牙周炎）中的贡献的第一次全面分析，并将为维生素D作为治疗剂的开发提供基础。

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, together with epidemiologic studies to characterize the relationship between vitamin D and the innate immune defense in periodontal disease. We propose three 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 to1,25(OH)2D3 with respect to transcriptional control of innate immune gene expression. 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. 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 effec 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 supplement both local and systemic vitamin D levels to quantify the effect of increased concentrations on the innate immune defenses. 3. Determine the relationship between serum vitamin D levels and periodontal disease in humans. We hypothesize that vitamin D can affect the onset and severity of periodontal disease in humans by the regulation of innate immune defenses. We will quantify the correlation between the severity of periodontal disease and serum vitamin D levels. These levels will also be correlated with changes in the subgingival microbiota. While long examined for its role in human health, the results we expect to obtain from this study would represent the first comprehensive analysis of the contribution of vitamin D in a chronic infectious disease such as periodontitis, and will provide the basis for the development of vitamin D as a therapeutic agent.