Mechanisms and Treatment Response of Aggressive Periodontitis in Children

儿童侵袭性牙周炎的发病机制和治疗效果

• 批准号: 9258317
• 负责人: Luciana Macchion Shaddox
• 金额: $ 70.29万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9258317
• 关键词: Affect; African American; Aftercare; Age; Cardiovascular Diseases; Child; Child health care; Childhood; Chronic; Clinical; Cytokine Gene; DNA Methylation; Data; Dental Care; Diabetes Mellitus; Diagnosis; Disease; Endotoxins; Epigenetic Process; Evaluation; Event; Florida; Future; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Goals; Health; Incisor; Individual; Inflammation; Inflammatory; Inflammatory Response; Inherited; Lead; Left; Life; Low Prevalence; Methylation; MicroRNAs; Modification; Nature; Participant; Patients; Periodicity; Periodontal Diseases; Periodontitis; Population; Predisposition; Prevention; Promoter Regions; Receptor Signaling; Recruitment Activity; Recurrence; Regulation; Risk; Role; Siblings; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Systemic disease; Toll-like receptors; Tooth Loss; Underserved Population; Work; aged; base; chemokine; cohort; cytokine; disorder prevention; disorder risk; epigenetic regulation; histone modification; improved outcome; new therapeutic target; novel diagnostics; peripheral blood; public health relevance; treatment response

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.

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两个卫生部门服务不足的非洲裔美国人，他们被诊断患有罕见的侵袭性牙周病，称为局部侵袭性牙周炎（LAP）。尽管其患病率很低，但我们收集了来自100多名LAP受试者的队列数据，这些受试者在缺乏针对这种疾病的专门牙科护理的人群中。具体来说，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相关。重要的是，在一些牙周健康的LAP患者的兄弟姐妹中也观察到这种高反应性，这表明这些个体可能具有遗传获得性和/或受调节的疾病易感性。因此，本提案的目标是扩展我们的发现，并研究遗传基因对LAP条件下tlr诱导的高炎症反应的调控，以及tlr诱导的高炎症反应的表观遗传调控。重要的是，这些因素与治疗反应和长期稳定性的关系也将被确定。具体而言，我们将扩大我们的临床中心以招募新的受试者，以达到总共200例LAP病例，200例年龄匹配的LAP受试者的健康兄弟姐妹和200例不相关的健康对照，年龄在5-25岁，全身健康的非洲裔美国人。我们将进行临床检查并收集所有受试者的外周血，以达到以下3个目标：1-评估与LAP高炎症相关的特异性toll样受体（TLR）和细胞因子单核苷酸多态性（snp）；2-描述LAP中与tlr诱导的高反应性相关的信号事件；3-研究不同表观遗传修饰在LAP中tlr诱导的高反应性调控中的作用。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会改善牙周治疗的结果，而且对于预防LAP中观察到的疾病复发的周期性性质以及健康易感个体的疾病起始是必不可少的。此外，了解这种侵袭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意义，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LAP的预防和成功的长期管理带来新的诊断和治疗靶点。