Molecular control of bone development and inflammation by FBXO11

FBXO11 对骨发育和炎症的分子控制

基本信息

批准号：
10155459
负责人：
Jia Chang
金额：
$ 36.22万
依托单位：
UNIVERSITY OF FLORIDA
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：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10155459
关键词：
Address Adult Affect Aging Alveolar Bone Loss Animal Model Animals Antidepressive Agents Apoptosis B cell differentiation Bacteria Biological Process Bone Development Bone Diseases Bone Growth Bone Marrow Bone Regeneration Bone Resorption Bone Transplantation Bone remodeling Carcinoma Cell Culture Techniques Cell Cycle Regulation Cells Chronic Clinical Research Code Data Dental Implants Differentiation and Growth Disease Economic Burden F Box Domain F-Box Proteins FDA approved Failure Genes Genetic Engineering Genomics Growth Health Human Implant In Vitro Infection Inflammation Inflammatory Intervention KDM1A gene Knock-out Knockout Mice Lipopolysaccharides Mediating Mesenchymal Stem Cells Modeling Molecular Mus Oral Oral cavity Osteitis Osteoblasts Osteogenesis Otitis Media Pathway interactions Patients Periodontitis Pharmaceutical Preparations Play Porphyromonas gingivalis Prevalence Proteins Quality of life Regulation Regulatory Pathway Risk Role Signal Transduction Signaling Molecule Site Snails Systemic disease Tooth Loss Tooth structure Transgenes Transplantation aged alveolar bone bone bone loss bone metabolism cell motility experimental study gene therapy health economics in vivo in vivo Model inflammatory bone loss inflammatory milieu inhibitor/antagonist innovation knock-down melanocyte mouse model new therapeutic target novel osteoblast differentiation osteogenic overexpression peri-implantitis prevent subcutaneous therapeutic target tumor progression young adult

项目摘要

Project Summary Chronic inflammation disrupts bone metabolism and promotes bone loss. Periodontitis and peri-implantitis are the most common inflammatory bone diseases in the oral cavity. In such an inflammatory environment, bone formation and bone resorption uncouple, leading to inflammatory bone damage, tooth loss, and dental implant failure. In this study, we propose a novel mechanism by which F-BOX Protein11 (FBXO11) regulates bone development and inflammation. FBXO11 is a protein-coding gene associated with otitis media. Additionally, it functions in a broad range of biological processes including melanocyte apoptosis, cell cycle regulation, cell migration, B-cell differentiation, and epithelial cancer progression. However, the effect of FBXO11 on bone development and inflammation has not been determined. Our preliminary studies in murine osteoblasts and genomic animal model showed that FBXO11 is a critical signaling molecule governing osteogenic differentiation by inhibiting Snail1/ lysine-specific demethylase 1 (LSD1). Furthermore, we found that the FBXO11/Snail1/LSD1 signaling axis is an important mechanism underlying inflammatory bone loss in cases of chronic inflammation, such as periodontitis and peri- implantitis. The novel mechanisms identified in our proposed studies will be critical for developing molecular strategies to prevent bone loss and promote bone regeneration in periodontal and peri-implant infection. Three specific aims will address the overarching hypothesis that FBXO11 regulates osteogenic differentiation in bone development and inflammation. Specific Aim1 will determine if FBXO11 is essential for osteogenic differentiation and bone growth by using FBXO11- overexpressing and knockdown osteogenic cells cultures, bone transplant experiment, and a conditional FBXO11 knockout mouse model. Specific Aim 2 will determine if FBXO11/Snail1/LSD1 regulatory axis contributes to inflammatory bone remodeling in the polymicrobial periodontitis and peri-implantitis animals. Specific Aim 3 will determine if we can render this FBXO11 axis as novel targets to treat periodontitis and peri-implantitis that represent significant health and economic burden world widely. We propose two innovative approaches, gene therapy by genetically engineering FBXO11 transgene in osteoblasts and a local intervention with a specific LSD1 inhibitor trans-2-phenylcyclopropylamine (2-PCPA), an FDA-approved antidepressant medication to prevent bone loss and promote bone regeneration. If this proposed study validates our hypothesis of repurposing of 2-PCPA to treat inflammatory bone disease, we will consider advancing the use of 2-PCPA to treat chronic periodontitis and peri-implantitis into clinical studies.

项目概要慢性炎症会破坏骨代谢并促进骨质流失。牙周炎和种植体周围炎是口腔中最常见的炎症性骨病。在这样的炎症环境下，骨形成和骨吸收脱节，导致炎症性骨损伤、牙齿脱落和牙种植失败。在这项研究中，我们提出了 F-BOX Protein11 (FBXO11) 调节骨的新机制发育和炎症。 FBXO11 是一种与中耳炎相关的蛋白质编码基因。此外，它在广泛的生物过程中发挥作用，包括黑素细胞凋亡、细胞周期调节、细胞迁移、B 细胞分化和上皮癌进展。然而，效果 FBXO11 对骨骼发育和炎症的影响尚未确定。我们的初步研究小鼠成骨细胞和基因组动物模型表明 FBXO11 是一种关键的信号分子通过抑制 Snail1/赖氨酸特异性去甲基酶 1 (LSD1) 来控制成骨分化。此外，我们发现FBXO11/Snail1/LSD1信号轴是一个重要的机制在慢性炎症（例如牙周炎和牙周炎）的情况下，潜在的炎症性骨质流失种植体炎。我们提出的研究中确定的新机制对于开发分子生物学至关重要在牙周和种植体周围感染中预防骨质流失并促进骨再生的策略。三具体目标将解决FBXO11调节骨成骨分化的总体假设发育和炎症。具体目标1将确定FBXO11是否对于成骨至关重要通过使用 FBXO11 过度表达和敲低成骨细胞培养物进行分化和骨生长，骨移植实验和条件FBXO11基因敲除小鼠模型。具体目标 2 将确定是否 FBXO11/Snail1/LSD1 调节轴有助于多种微生物的炎症骨重塑牙周炎和种植体周围炎动物。具体目标 3 将确定我们是否可以将此 FBXO11 轴渲染为治疗牙周炎和种植体周围炎的新目标，这些疾病带来了巨大的健康和经济负担世界广泛。我们提出了两种创新方法，通过基因工程FBXO11进行基因治疗成骨细胞转基因和特定 LSD1 抑制剂反式 2-苯基环丙胺的局部干预 (2-PCPA)，一种 FDA 批准的抗抑郁药物，可防止骨质流失并促进骨再生。如果这项拟议的研究验证了我们重新利用 2-PCPA 治疗炎症性骨病的假设，我们将考虑推进2-PCPA治疗慢性牙周炎和种植体周围炎的临床应用研究。