Mechanisms and Treatment Response of Aggressive Periodontitis in Children

描述(由申请人提供)：通过本申请的前身(R01DE019456)，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口，他们被诊断为一种罕见的侵袭性牙周病，称为局限性侵袭性牙周炎(LAP)。尽管其患病率很低，但我们从100多名LAP受试者中收集了数据，这些人群缺乏对这种疾病的专门牙科护理。具体地说，我们在这些受试者中发现了TLR诱导的高炎症反应，这与疾病表现和全身内毒素水平有关。重要的是，这种高反应性也在LAP受试者的一些周期性健康的兄弟姐妹中观察到，这表明这些人有潜在的遗传获得性和/或受调控的疾病易感性。因此，本提案的目的是扩大我们的发现，并研究遗传基因对LAP条件下TLR诱导的高炎症反应参与炎症信号调节的遗传贡献，以及表观遗传学调节。重要的是，还将确定这些因素与治疗反应和长期稳定性的关联。具体地说，我们将扩大我们的临床中心，招募新的受试者，总共200名LAP病例，200名年龄匹配的LAP患者的健康同胞和200名无关的健康对照，年龄在5-25岁之间，系统健康的非裔美国人。我们将进行临床检查并采集所有受试者的外周血，以具体达到这三个目标：1-评估与LAP中高炎症状态相关的特异性Toll样受体(TLR)和细胞因子单核苷酸多态性(SNPs)；2-描述与TLR诱导的LAP高反应性相关的信号事件；以及3-研究不同的表观遗传修饰在调节TLR诱导的LAP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被评估。对这些机制的评估不仅将改善牙周治疗的结果，而且对于防止在LAP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也是必不可少的。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具有巨大的影响，因为高炎症还涉及其他系统性疾病，如糖尿病和心血管疾病。重要的是，这项建议的结果将有望为LAP的预防和成功的长期治疗带来新的诊断和治疗目标。

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.