Vitamin D and Periodontal Disease

描述(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。作为一项名为“维生素D诱导牙龈细胞中的抗菌活性”的R21资助的结果，e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，从而增加对周围致病细菌的抗菌天然免疫防御。其他研究表明，维生素D水平和宿主对口腔感染的抵抗力之间存在很强的关联。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。为了解决这一假说，我们建议对这种关系进行全面的分析，包括体外和体内实验分析，以表征维生素D与牙周病的天然免疫防御之间的关系。我们提出了两个目标：1.研究维生素D诱导牙龈上皮细胞天然免疫的机制。通过定义1，25(OH)2D3对天然免疫基因表达的转录调控以及与天然免疫应答途径的相互作用，我们将更好地理解这种诱导。这将是第一次表征口腔上皮细胞中与维生素D相关的分子通路，以及与先天免疫通路的相互作用。这样做将对口腔内的先天免疫有更好的了解。2.在细菌诱导的牙周病小鼠模型中，量化维生素D与牙周病的关系。我们假设，调节血清维生素D水平与牙龈上皮的天然免疫防御能力直接相关。为了在体内证实这一点，我们将在以细菌为基础的牙周病小鼠模型中确定维生素D耗尽的影响。由于小鼠的LL-37同源物不是由维生素D诱导的，我们也将使用一种人源化的菌株，它在自己的(人的，维生素D调节的)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性免疫防御的影响。虽然我们长期研究维生素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着对维生素D对预防牙周炎等慢性传染病的贡献的第一次机制分析，并将为维生素D作为治疗剂的发展提供基础。 公共卫生相关性：牙周病是由附着并定植在牙齿附近的牙龈细胞的细菌引起的。我们发表的由R21资助的结果表明，维生素D可以增强牙龈细胞对与牙周病相关的细菌的免疫防御。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。这一结果将支持维生素D作为牙周病和其他口腔感染的治疗方法的发展。

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.