Mechanisms and Treatment Response of Aggressive Periodontitis in Children

描述（由申请人提供）：通过本申请的前申请（R 01 DE 019456），我们一直在评估北佛罗里达州两个卫生部门服务不足的非裔美国人人群，他们被诊断患有一种不常见的侵袭性牙周病，称为局部侵袭性牙周炎（Localized aggressive periodontitis，简称RAPD）。尽管其患病率低，我们已经收集了来自100多名牙科受试者的队列数据，这些受试者缺乏针对这种疾病的专门牙科护理。具体而言，我们已经发现TLR诱导的高度炎症反应在这些受试者中，这与疾病表现和全身内毒素水平相关。重要的是，这种高反应性也观察到在牙周健康的兄弟姐妹的牙周病受试者，表明潜在的遗传获得性和/或调节易感性的疾病在这些人。因此，本提案的目标是扩展我们的发现，并研究遗传基因对炎症信号转导的调节的贡献，以及在炎症条件下TLR诱导的过度炎症反应的表观遗传调节。重要的是，还将确定这些因素与治疗反应和长期稳定性的相关性。具体而言，我们将扩大我们的临床中心，招募新受试者，以达到总共200例受试者，200例受试者的年龄匹配的健康兄弟姐妹和200例无关的健康对照，非裔美国人，年龄5-25岁，全身健康。我们将进行临床检查并收集所有受试者的外周血，以具体达到以下3个目的：1-评估与SLE高炎症特征相关的特异性TLR和细胞因子单核苷酸多态性（SNP）; 2-描述与TLR诱导的SLE高反应性相关的信号事件;和3-检查多种表观遗传修饰在调节TLR诱导的高反应性中的作用。重要的是，牙周治疗对观察到的现象的影响也将进行评估。对这些机制的评估不仅会改善牙周治疗的结果，而且对于预防牙周炎中观察到的疾病复发的周期性以及健康易感个体的疾病起始至关重要。此外，了解这种侵略性炎症反应背后的机制对这些儿童未来的健康有着巨大的影响，因为过度炎症也涉及其他全身性疾病，如糖尿病和心血管疾病。重要的是，这项提议的结果有望为预防和成功长期管理糖尿病带来新的诊断和治疗靶点。

DESCRIPTION (provided by applicant): Through the predecessor to this application (R01DE019456) we have been evaluating an underserved population of African-Americans in two health departments in North-Florida, diagnosed with an uncommon, aggressive form of periodontal disease known as localized aggressive periodontitis (LAP). Despite its low prevalence, we have compiled data from a cohort of over 100 LAP subjects, amongst a population which lacks specialized dental care for this disease. Specifically, we have discovered a TLR-induced hyper-inflammatory response in these subjects, which correlates with disease presentation and systemic levels of endotoxin. Importantly, this hyper-responsiveness is also observed in some periodontally healthy siblings of LAP subjects, indicating a potential genetically acquired and/or regulated predisposition for disease in these individuals. Therefore, the goal of this proposal is to expand on our discoveries and investigate inherited genetic contributions to regulation of inflammatory signaling involved in, and epigenetic regulation of thi TLR-induced hyper-inflammatory response under the condition of LAP. Importantly, association of these factors with treatment response and long-term stability will also be determined. Specifically, we will be expanding our clinical centers to recruit new subjects to reach a total of 200 LAP cases, 200 age-matched healthy siblings of LAP subjects and 200 unrelated healthy controls, African- Americans, aged 5-25 years old, and systemically healthy. We will and perform clinical examination and collect peripheral blood from all subjects to specifically reach these 3 aims: 1- Evaluate specific toll-like receptor (TLR) and cytokine Single Nucleotide Polymorphisms (SNPs) associated with hyper-inflammatory profile in LAP; 2- Delineate the signaling events associated with TLR-induced hyper-responsiveness in LAP; and 3- Examine the role of diverse epigenetic modifications in the regulation of TLR-induced hyper-responsiveness in LAP. Importantly, the effect of periodontal therapy on the observed phenomenon will also be evaluated. Evaluation of these mechanisms will not only lead to improved outcomes of periodontal therapy, but are imperative for the prevention of the cyclical nature of disease recurrence observed in LAP, as well as disease initiation in healthy susceptible individuals. Furthermore, understanding the mechanisms behind this aggressive inflammatory response has enormous implications in the future health of these children, as hyper- inflammation is also involved in other, systemic, diseases such as diabetes and cardiovascular disease. Importantly, results from this proposal will hopefully lead to novel diagnostic and therapeutic targets for the prevention and successful long-term management of LAP.