Methylation signaling in periodontal health and disease

项目摘要 牙周炎是人类第二大传染病。它是一种慢性炎症性疾病 导致牙齿支撑结构的破坏，包括牙龈，牙周膜和 牙槽骨它是牙齿脱落的主要原因，并引起全身性影响，包括心血管 疾病、早产和癌症。虽然微生物生物膜是牙周炎的主要原因， 越来越认识到宿主的炎症反应决定牙周病的结果。 因此，阐明控制炎症反应的分子信号传导网络对于 了解和治疗这种疾病。控制炎症的信号网络失调 通常是牙周炎的病因。Toll样受体（TLR）信号传导是主要的促炎途径， 而转化生长因子β（transforming growth factor β，TGFβ）信号转导是主要的抗炎途径。平衡 TLR和TGFβ的促炎和抗炎信号传导网络定义了免疫应答。在败血症和 在血管炎症中，TGFβ诱导的TLR信号传导抑制通过诱导抑制性 Smad6.在牙周组织中，我们发现Smad 6在牙龈上皮中高表达， Smad 6活性的增加加重了牙周骨丢失，表明TGFβ-引起TLR信号转导的抑制 可能通过调控牙龈上皮信号网络调控牙周炎。我们调查 Smad 6在牙龈上皮细胞中的作用机制，并确定了一个新的信号级联步骤， TLR抑制涉及Smad 6甲基化。我们假设Smad 6甲基化抑制了 牙龈上皮炎症通过开启维持内环境稳定和改善牙周炎 TGFβ诱导TLR信号转导的抑制。我们建议使用小鼠遗传模型（目标1和2）， 研究Smad 6甲基化在牙周稳态和疾病中作用，以及细胞和生化 方法（目的3）了解牙周炎的分子调控机制 应答这种涉及Smad 6甲基化的新机制是TLR信号传导中以前未知的步骤 调节，并引入具有治疗潜力的新的干预点。

PROJECT SUMMARY ABSTRACT Periodontitis is the second most prevalent infectious disease of mankind. It is a chronic inflammatory condition that leads to the destruction of tooth-supporting structures, including the gingiva, periodontal ligament and alveolar bone. It is the main cause of tooth loss and induces systemic implications, including cardiovascular disorders, preterm birth and cancer. While a microbial biofilm is the main cause of periodontitis, it is increasingly recognized that the host inflammatory responses determine the outcome of periodontal disease. Therefore elucidation the molecular signaling network controlling inflammatory responses is crucial for understanding and treating this disease. Dysregulation of signaling networks that serve to control inflammation is often causative for periodontitis. Toll-like receptor (TLR) signaling is the master pro-inflammatory pathway, while transforming growth factor β (TGFβ) signaling is a major anti-inflammation pathway. Balance between pro- and anti-inflammation signaling networks of TLR and TGFβ defines the immune responses. In sepsis and vascular inflammation, TGFβ-elicited inhibition of TLR signaling occurs through the induction of inhibitory Smad6. In periodontal tissues, we found that Smad6 is highly expressed in gingival epithelium and disturbance of Smad6 activity exacerbated periodontal bone loss, suggesting that TGFβ-elicited inhibition of TLR signaling may regulate periodontitis through controlling gingival epithelial signaling network. We investigated mechanisms of Smad6 action in gingival epithelial cells and identified a novel step in signaling cascades for TLR inhibition that involves Smad6 methylation. We hypothesize that Smad6 methylation suppresses inflammation in gingival epithelium to maintain homeostasis and ameliorate periodontitis through switching on TGFβ-elicited inhibition of TLR signaling. We propose to use mouse genetic models (Aim 1 and 2) to investigate roles of Smad6 methylation in periodontal homeostasis and disease, and cell and biochemical approaches (Aim 3) to understand the molecular regulatory mechanisms of periodontal inflammatory responses. This novel mechanism involving Smad6 methylation is a previously unknown step in TLR signaling regulation and introduces new point of intervention with therapeutic potential.