Vitamin D and Periodontal Disease

描述（由申请人提供）：口腔上皮的先天免疫是抵御引起牙周病的病原微生物的第一道防线。根据一项名为“维生素D诱导牙龈细胞的抗菌活性”的R21资助，我们最近发现口腔上皮细胞能够将无活性的维生素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，从而增加对周围致病菌的抗菌先天免疫防御。其他研究表明，维生素D水平与宿主对口腔感染的防御能力之间存在很强的联系。这些数据为我们的假设提供了强有力的支持，即维生素D促进了牙龈上皮的先天免疫防御。为了解决这一假设，我们提出了一种全面的关系分析，包括体外和体内实验分析，以表征维生素D与牙周病先天免疫防御之间的关系。我们提出两个目标：1。表征维生素d介导的牙龈上皮细胞（GEC）先天免疫诱导机制。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的相互作用，我们将更好地理解诱导。这将是首次表征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的相互作用。这样做可以更好地了解口腔内的先天免疫。2. 在细菌诱导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缺失的影响。由于与LL-37的小鼠同源物不是由维生素D诱导的，我们还将使用一种人源化菌株，在其自身（人类，维生素D调节）启动子的控制下表达LL-37。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。虽然长期以来人们一直在研究维生素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首次对维生素D在防御慢性传染病（如牙周炎）方面的作用进行机制分析，并将为维生素D作为治疗剂的发展提供基础。

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 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.