Mechanism of Bone Resorption in Periodontitis

牙周炎骨吸收机制

基本信息

批准号：
9883634
负责人：
Yasuyoshi Ueki
金额：
$ 39.38万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9883634
关键词：
Adaptor Signaling Protein Address Adult Affect Alveolar Bone Loss Bone Resorption Cherubism Child Communicable Diseases DNA Sequence Alteration Data Disease Gene Mutation Genetic Diseases Gingiva Goals Health Health Expenditures Hereditary Disease Human Immune response Inflammation Inflammation Mediators Inflammatory Knock-in Mouse Knock-out Knockout Mice Lesion Ligature Malignant Neoplasms Mandible Maxilla Mediator of activation protein Molecular Mus Mutation Myeloid Cells Online Mendelian Inheritance In Man Oral Osteoclasts Pathogenesis Pathologic Pathway interactions Patients Periodontal Diseases Periodontitis Pharmacotherapy Phosphotransferases Play Pneumonia Population Predisposition Production Protein Binding Domain Quality of life Rare Diseases Regulation Rheumatoid Arthritis Role SH3 Domains SYK gene Severities Signal Transduction TLR2 gene TNF gene Testing Therapeutic Tissues Tooth Loss alveolar bone base bone bone loss cardiovascular disorder risk craniofacial disorder design gain of function gain of function mutation gene discovery inflammatory bone loss inhibitor/antagonist insight loss of function loss of function mutation macrophage mouse model mutant neutrophil novel oral bacteria oral infection osteoclastogenesis pathogenic bacteria public health relevance rare condition response

项目摘要

DESCRIPTION (provided by applicant): Periodontitis is an oral inflammatory disease resulting in swollen gingiva and tooth loss due to resorption of alveolar bones, which reduce the quality of life. Over 47% of adult U.S. population has periodontitis. Periodontitis can also increase risk for cardiovascular disease and rheumatoid arthritis. Studies have suggested that a pathologic immune response to oral bacteria is primarily responsible for periodontitis and subsequent activation of osteoclasts, resulting in alveolar bone loss. However, the mechanisms of the induction of bone resorption in periodontitis are not fully understood. Therefore, the goal of this proposal is to identify and characterize the molecular and cellular mechanisms responsible for bone resorption in this poor condition. Our discovery of the gene mutations responsible for a rare craniofacial disorder "Cherubism" may provide novel insights into the mechanisms. Cherubism is a genetic disorder characterized by excessive destruction of mandibular and maxillary bones due to proliferation of inflammatory lesions containing a large number of osteoclasts. We have previously discovered that gain-of-function mutations in the signaling adaptor protein SH3-domain binding protein 2 (SH3BP2) are responsible for this rare condition. The mouse model of cherubism showed that the mutation increases responsiveness to bacterial pathogens and enhances tumor necrosis factor (TNF)-α production by macrophages. Hyper-activation of the toll-like receptor 2 and 4 by SYK kinase that interacts with mutant SH3BP2 is a major initiator of inflammation. Furthermore, we have discovered that gain- and loss-of-function of SH3BP2 respectively increases or decreases osteoclast formation in response to TNF-α. Recently, these studies have taken an exciting new direction based on our new discovery that SH3BP2 gain- and loss-of-function mutations have a profound effect on susceptibility to bone loss in a mouse model of periodontitis. This elevates the significance of SH3BP2 beyond its role in a rare inherited disorder and suggests that SH3BP2 is a critical player in inflammation and bone resorption in periodontitis. Therefore, our data have led us to a new hypothesis that SH3BP2 is responsible for the regulation of osteoclast activity during the progression of periodontitis resulting in alveolar bone loss. To test the hypothesis, the three specific aims are proposed: Aim 1) Determine the mechanism by which SH3BP2 gain-of-function increases bone loss in periodontitis. Aim 2) Determine the mechanism by which SH3BP2 loss- of-function protects against bone loss in periodontitis. Aim 3) Determine the effect of SYK inhibition on bone resorption in periodontitis. Completion of the proposed specific aims will further delineate the role of SH3BP2 as a key signaling mediator of inflammatory bone loss in periodontitis and will identify its downstream inflammatory mediators important for osteoclastogenesis. Confirmation that loss-of-function of SH3BP2 or inhibition of its downstream mediator SYK can protect against periodontitis-associated bone loss will open up new opportunities for targeting these pathways therapeutically for the treatment of periodontitis.

描述（由申请人提供）：牙周炎是一种口腔炎症性疾病，会因牙槽骨吸收而导致牙龈肿胀和牙齿脱落，从而降低生活质量。超过 47% 的美国成年人患有牙周炎。心血管疾病和类风湿性关节炎研究表明，对口腔细菌的病理性免疫反应是牙周炎和随后破骨细胞激活的主要原因。然而，牙周炎中诱导骨吸收的机制尚不完全清楚，因此，本提案的目的是确定和表征在这种不良情况下导致骨吸收的分子和细胞机制。导致罕见颅面疾病“Cherubism”的基因突变的发现可能会为其机制提供新的见解。Cherubism是一种遗传性疾病，其特征是由于含有一种炎症病变的增殖而导致下颌骨和上颌骨过度破坏。我们之前发现，信号接头蛋白 SH3 结构域结合蛋白 2 (SH3BP2) 的功能获得性突变是造成这种罕见病症的原因，天使小鼠模型表明，该突变增加了对细菌的反应性。与突变型 SH3BP2 相互作用的 SYK 激酶可过度激活 Toll 样受体 2 和 4。此外，我们发现 SH3BP2 的功能获得和丧失分别会增加或减少对 TNF-α 的破骨细胞形成，最近，这些研究基于我们的新发现取得了令人兴奋的新方向。 SH3BP2 功能获得和丧失突变对牙周炎小鼠模型中骨质流失的易感性具有深远影响，这使 SH3BP2 的重要性超出了其在罕见遗传性疾病中的作用，并表明： SH3BP2 在牙周炎的炎症和骨吸收中发挥着关键作用，因此，我们的数据使我们提出了一个新的假设，即 SH3BP2 在牙周炎进展过程中负责调节破骨细胞活性，从而导致牙槽骨丢失。提出了三个具体目标：目标 1) 确定 SH3BP2 功能获得增加牙周炎骨质流失的机制。 SH3BP2 功能丧失可防止牙周炎中的骨丢失。目标 3) 确定 SYK 抑制对牙周炎中骨吸收的影响。特定目标的完成将进一步阐明 SH3BP2 作为炎症性骨丢失的关键信号传导介质的作用。在牙周炎中，将鉴定其对破骨细胞生成重要的下游炎症介质，确认 SH3BP2 功能丧失或抑制其下游介质。 SYK 可以防止牙周炎相关的骨质流失，这将为针对这些途径治疗牙周炎开辟新的机会。