Endogenous Regulators of Inflammation in Periodontal Tissue Homeostasis

针对内源性调节因子的策略已经出现，以限制炎症和保存组织 动态平衡开启慢性感染性和炎症性疾病治疗的新范式 包括牙周病。泛素化是一种可逆的翻译后修饰，可以终止 细胞信号通过蛋白酶体介导的降解，也参与蛋白质的运输和激活 因此在多种炎症信号的调节中起关键作用 瀑布。虽然泛素化对于激活免疫反应是必不可少的，但它的严格调控和及时 终止是控制潜在的破坏性炎症信号和保存组织的关键 动态平衡。因此，泛素化和泛素相关事件在功能调节中是必不可少的。 免疫细胞可塑性和动态平衡事件。然而，目前还没有研究对它们的作用进行研究 对口腔粘膜的影响。最近，A20(也称为肿瘤坏死因子α诱导蛋白3或TNFAIP3)已经出现为 通过干扰泛素化来抑制炎症的关键负性调节因子。A20位于Toll的下游 TLRs、NOD样受体、T细胞受体和细胞因子受体(如TNFR、IL-1R、IL-17R) 它主要通过限制NF-κB途径来调节炎症，并调节其他细胞功能，如 细胞凋亡、坏死性下垂和自噬。通过其在一系列不同的生物机制中的作用，A20是 与胃肠道、心血管和肺部疾病、自身免疫和神经疾病有关 疾病，类风湿性关节炎，衰老，主要是癌症。同样，我们现在有证据支持 假设A20是口腔粘膜内的关键调节因子之一，并充当 通过干预关键的上下游事件来限制牙周炎症。整体而言 当前提案的目标是描述泛素化的作用，并特别关注其功能 以及A20在宿主-口腔微生物组相互作用中的调控，因为它们与关键的细胞和分子相关 牙周炎病程中的途径。我们试图发现口腔内以前未被探索过的区域。 通过进行涉及临床研究和良好特征的临床前研究的补充实验 疾病模型。拟议的研究有望揭示新的生物学和机械学见解，并 不仅对牙周病，而且对其他局部感染驱动的新概念和治疗方法 炎症状况以及与帕金森病相关的疾病，如口腔恶性肿瘤和衰老 相关条件。

Strategy of targeting endogenous regulators has emerged to limit inflammation and preserve tissue homeostasis opening a new paradigm in the treatment of chronic infectious and inflammatory conditions including periodontal disease. Ubiquitination is a reversible post-translational modification that can terminate cell signaling through proteasome-mediated degradation and also involved in protein trafficking and activation of kinases and phosphatases thereby playing a key role in the regulation of multiple inflammatory signaling cascades. While ubiquitination is essential to activate immune responses, its tight regulation and timely termination is the key to keep the potentially damaging inflammatory signals in check and preserve tissue homeostasis. Therefore, ubiquitination and ubiquitin-related events are essential in the regulation of functional immune cell plasticity and homeostatic events. However, there are yet no studies which investigated their role on the oral mucosa. Recently, A20 (also known as TNF alpha induced protein 3 or TNFAip3) has emerged as a critical negative regulator of inflammation through interfering with ubiquitination. A20 lies downstream of Toll like receptors (TLRs), NOD-like receptors, T cell receptor, and cytokine receptors (e.g. TNFR, IL-1R, IL-17R) and regulates inflammation mainly by restricting NF-κB pathway and modulates other cellular functions such as apoptosis, necroptosis and autophagy. Through its function in a diverse set of biological mechanisms, A20 is implicated in gastrointestinal, cardiovascular, and pulmonary diseases, autoimmune and neurological disorders, rheumatoid arthritis, aging and mostly in cancer. Likewise, we now have evidence supporting the hypothesis that A20 is one of the key regulatory factors within the oral mucosa and acts as a gatekeeper to restrict periodontal inflammation through interfering with critical upstream and downstream events. The overall goal of the current proposal is to delineate the role of ubiquitination with specific focus being on the function and regulation of A20 in host-oral microbiome interactions as they relate to the key cellular and molecular pathways in the course of periodontitis. We seek to uncover a previously unexplored area within the oral cavity through conducting complementary experiments involving clinical studies and well characterized preclinical disease models. The proposed studies are expected to unveil novel biological and mechanistic insights and lead to new concepts and therapeutics not only for periodontal disease but also for other local infection driven inflammatory conditions as well as diseases associated with PD such as oral cavity malignancies and aging related conditions.