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: 9311559
• 负责人: Tom Diekwisch
• 金额: $ 34.69万
• 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/9311559
• 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; Gene Targeting; 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; Stem cells; Testing; Therapeutic; Time; Tissue Engineering; Tissues; Tooth Loss; Tooth structure; Treatment Efficacy; Wound Healing; alveolar bone; base; bone; bone loss; combat; crosslink; design; improved; in vivo; inhibitor/antagonist; member; mineralization; novel; progenitor; restoration; scaffold; small molecule

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.

摘要 牙周组织再生，包括新牙槽骨的形成，以及 新的结缔组织附着的产生一直是牙周治疗的最终目标。 自1980年代以来的研究和治疗。在这里，我们已经确定了高度选择性的SETD 7 甲基转移酶活性抑制剂（R）-PFI-2（PFI-2）作为一种强大的小分子调节剂， 改善牙周炎的严重程度，显著促进牙槽骨的新生 形成、新牙骨质形成和牙周膜再附着。当PFI-2 应用于我们的啮齿动物模型中的牙周缺损， 牙槽骨高度相当于人类附着水平垂直骨增加3 mm 与对照组相比。这些初步数据表明，PFI-2可能代表了一种新的 回答牙周再生的追求和一个分子能够倾斜牙周 体内平衡有利于合成代谢方面。解释PFI-2 影响牙周干细胞功能，我们的初步数据表明，PFI-2治疗， 增加YAP 1核转位和下游基因表达，表明PFI-2 通过一种新的途径影响炎症条件下牙周基因的表达， 包括甲基转移酶SETD 7和Hippo途径成员YAP 1。基于这些 令人兴奋的初步数据，我们现在假设PFI-2上调YAP 1靶基因 通过核转位表达，从而改善牙周祖细胞增殖 和分化，并减少炎症条件下的牙周骨丢失。我们 预计这些研究将导致开发新的小分子为基础的 用于治疗牙周病和对抗相关的牙周炎损失的治疗剂 牙周组织，这将有助于实践牙周病医生。