Small molecule mediated restoration of periodontal homeostasis through the YAP1 pathway

小分子通过 YAP1 途径介导牙周稳态恢复

• 批准号: 9892878
• 负责人: Tom Diekwisch
• 金额: $ 35.3万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-19 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892878
• 关键词: Affect; Alveolar Bone Loss; Bone Regeneration; Cell physiology; Cementum Formation; Chitosan; Collagen; Connective Tissue; Data; Defect; Dentists; Development; Disease; Effectiveness; Equilibrium; Gelatin; Gene Expression; Gene Expression Profiling; Generations; Goals; Height; Hemorrhage; Histologic; Homeostasis; Human; In Vitro; Inflammation; Inflammatory; Knockout Mice; Lead; Ligature; Mediating; Methylation; Methyltransferase; Modeling; Nanosphere; Natural regeneration; Nuclear Translocation; Osteogenesis; Pain; Pathway interactions; Patients; Periodontal Diseases; Periodontal Ligament; Periodontitis; Phenotype; Porifera; Research; Rodent Model; Role; Severities; Side; Testing; Therapeutic; Time; Tissue Engineering; Tissues; Tooth Loss; Tooth structure; Treatment Efficacy; alveolar bone; base; bone; bone loss; combat; conditional knockout; crosslink; design; experimental group; improved; in vivo; inhibitor/antagonist; member; mineralization; novel; progenitor; restoration; scaffold; small molecule; stem cell homeostasis; stem cells; wound healing

Abstract Regeneration of periodontal tissues including formation of new alveolar bone, and generation of new connective tissue attachment have been the ultimate goals of periodontal research and therapy since the 1980ies. Here we have identified the highly selective SETD7 methyltransferase activity inhibitor (R)-PFI-2 (PFI-2) as a powerful small molecule modulator that ameliorated the severity of periodontal inflammation and significantly promoted new alveolar bone formation, new cementum formation, and periodontal ligament re-attachment. When PFI-2 was applied to periodontal defects in our rodent model, there was a substantial 1.7-fold increase in alveolar bone height equivalent to a 3 mm gain in vertical bone of attachment levels in humans when compared to controls. These preliminary data indicate that PFI-2 might represent a new answer to the quest for periodontal regeneration and a molecule capable of tipping the periodontal homeostasis balance in favor of the anabolic side. Explaining the mechanisms by which PFI-2 affects periodontal stem cell function, our preliminary data have demonstrated that PFI-2 treatment increased YAP1 nuclear translocation and downstream gene expression, suggesting that PFI-2 affects periodontal gene expression under inflammatory conditions through a novel pathway that includes the methyltransferase SETD7 and the Hippo pathway member YAP1. Based on these exciting preliminary data we have now hypothesized that PFI-2 upregulates YAP1 target gene expression through nuclear translocation, resulting in improved periodontal progenitor proliferation and differentiation, and reduced periodontal bone loss under inflammatory conditions. We anticipate that these studies will result in the development of novel small molecule-based therapeutics for the treatment of periodontal disease and to combat the associated loss of periodontal tissue that will aid the practicing periodontist.

抽象的 牙周组织的再生，包括形成新的肺泡骨和 产生新的结缔组织附件已成为牙周的最终目标 自1980年代以来的研究和治疗。在这里，我们确定了高度选择性的setd7 甲基转移酶活性抑制剂（R）-PFI-2（PFI-2）作为强大的小分子调节剂 改善了牙周炎症的严重程度，并显着促进了新的肺泡骨 形成，新的骨质形成和牙周韧带重新辅助。何时PFI-2是 应用于啮齿动物模型中的牙周缺陷，增加了1.7倍 牙槽骨高等效于人类垂直骨的3毫米增益 与对照组相比。这些初步数据表明PFI-2可能代表一个新的 回答寻求牙周再生和能够小费牙周的分子 稳态平衡​​支持合成代谢方面。解释PFI-2的机制 影响牙周干细胞功能，我们的初步数据表明PFI-2治疗 YAP1核转运和下游基因表达增加，表明PFI-2 通过新的途径在炎症条件下影响牙周基因表达 包括甲基转移酶SETD7和河马途径成员YAP1。基于这些 令人兴奋的初步数据我们现在假设PFI-2上调YAP1目标基因 通过核易位表达，从而改善了牙周祖细胞增殖 和分化，并减少炎症条件下的牙周骨质流失。我们 预计这些研究将导致新型基于小分子的发展 治疗牙周疾病的治疗剂，并打击相关的损失 牙周组织将有助于实践牙周病医生。