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Endogenous Regulators of Inflammation in Periodontal Tissue Homeostasis

牙周组织稳态炎症的内源性调节因子

基本信息

批准号：
10407028
负责人：
Sinem Esra Sahingur
金额：
$ 38.21万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10407028
关键词：
A20 protein Aging Alveolar Bone Loss Apoptosis Area Autoimmune Diseases Automobile Driving Autophagocytosis Bacteria Biological Biopsy Cardiovascular Diseases Cell physiology Cells Chronic Clinical Clinical Research Connective Tissue Cytokine Receptors Disease Disease Progression Disease model Enzymes Epigenetic Process Epithelial Event Flavonoids Focal Infection Gastrointestinal Diseases Gatekeeping Gene Delivery Genetic Genetic Transcription Gingiva Goals Homeostasis Human Immune Immune response In Vitro Inflammation Inflammatory Injections Knock-out Lead Lentivirus Lesion Ligature Lung diseases Malignant Neoplasms Mediating MicroRNAs Molecular Mus Myelogenous Oral Oral cavity Oral mucous membrane structure Pathogenicity Pathway interactions Periodontal Diseases Periodontitis Phosphoric Monoester Hydrolases Phosphotransferases Play Porphyromonas gingivalis Post-Translational Protein Processing Production Proteins Quercetin RNA Interference Regulation Rheumatoid Arthritis Role Signal Transduction Site System T-Cell Receptor TNF gene Therapeutic Time Tissue Preservation Tissues Toll-like receptors Tumor Necrosis Factor Receptor Ubiquitin Ubiquitination cell type clinically relevant cytokine differential expression disease phenotype experimental study immunoregulation in vivo in vivo Model insight intraperitoneal keratinocyte knock-down mRNA Expression macrophage multicatalytic endopeptidase complex nervous system disorder novel oral bacteria oral microbial community oral microbiome overexpression periodontopathogen pre-clinical protein activation protein transport receptor response

项目摘要

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.

针对内源性调节剂的策略已经出现，以限制炎症和保护组织体内平衡在慢性感染和炎性病症的治疗中开辟了新的范例包括牙周病。泛素化是一种可逆的翻译后修饰，通过蛋白酶体介导的降解的细胞信号传导，也参与蛋白质运输和活化从而在多种炎症信号的调节中发挥关键作用瀑布虽然泛素化对激活免疫反应至关重要，但其严格的调节和及时的免疫反应是至关重要的。终止是控制潜在的破坏性炎症信号和保护组织的关键体内平衡因此，泛素化和泛素相关的事件在功能调节中至关重要。免疫细胞可塑性和稳态事件。然而，目前还没有研究调查他们的作用，口腔粘膜上的最近，A20（也称为TNF α诱导蛋白3或TNFAip 3）已经出现，一个关键的负调节炎症通过干扰泛素化。A20位于Toll下游类受体（TLR）、NOD样受体、T细胞受体和细胞因子受体（例如TNFR、IL-1 R、IL-17 R）并主要通过限制NF-κB通路调节炎症，并调节其他细胞功能，凋亡、坏死性凋亡和自噬。通过其在多种生物机制中的功能，A20是涉及胃肠道、心血管和肺部疾病、自身免疫和神经系统疾病疾病，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，并作为守门人，通过干扰关键的上游和下游事件来限制牙周炎症。整体当前提案的目标是描述泛素化的作用，特别关注其功能和调节A20在宿主-口腔微生物组相互作用中的作用，因为它们涉及关键的细胞和分子生物学，牙周炎的发病机制我们试图揭示口腔内以前未被探索的区域通过进行涉及临床研究和充分表征的临床前研究的补充实验，疾病模型拟议中的研究有望揭示新的生物学和机械学见解，导致新的概念和治疗方法，不仅对牙周病，而且对其他局部感染驱动炎症性疾病以及与PD相关的疾病，如口腔恶性肿瘤和衰老相关条件。