Molecular control of bone development and inflammation by FBXO11

FBXO11 对骨发育和炎症的分子控制

• 批准号: 10615606
• 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
• 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/10615606
• 关键词: 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 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 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; Modeling; Molecular; Mus; Oral; Oral cavity; Osteitis; Osteoblasts; Osteogenesis; Otitis Media; Pathway interactions; Patients; Periodontitis; Pharmaceutical Preparations; Porphyromonas gingivalis; Prevalence; Proteins; Quality of life; Regulation; Regulatory Pathway; Risk; Signal Transduction; Signaling Molecule; Site; Snails; Systemic disease; Tooth Loss; Tooth structure; Transgenes; Transplantation; aged; alveolar bone; bone; bone loss; bone marrow mesenchymal stem cell; bone metabolism; bone repair; cell motility; experimental study; gene therapy; in vivo; in vivo Model; inflammatory bone loss; inflammatory milieu; inhibitor; innovation; knock-down; melanocyte; mouse model; new therapeutic target; novel; osteoblast differentiation; osteogenic; overexpression; peri-implantitis; prevent; subcutaneous; therapeutic target; tumor progression; validation studies; young adult

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.

项目摘要 慢性炎症破坏骨代谢，促进骨丢失。牙周炎和种植体周围炎是 口腔中最常见的炎症性骨病。在这样的炎症环境中， 形成和骨吸收分离，导致炎症性骨损伤、牙齿脱落和牙种植体 失败在这项研究中，我们提出了一种新的机制，F-BOX蛋白11（FBXO 11）调节骨 发育和炎症。FBXO 11是一个与中耳炎相关的蛋白质编码基因。 此外，它在广泛的生物学过程中发挥作用，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。但是，效果 FBXO 11对骨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，FBXO 11是一个关键的信号分子， 通过抑制Snail 1/赖氨酸特异性脱甲基酶1（LSD 1）来控制成骨分化。 此外，我们发现FBXO 11/Snail 1/LSD 1信号轴是一个重要的机制， 在慢性炎症的情况下，如牙周炎和牙周炎， 种植体炎我们提出的研究中发现的新机制对于开发分子生物学至关重要 预防牙周和种植体周围感染的骨丢失和促进骨再生的策略。三 具体的目标是解决FBXO 11调节骨成骨分化的总体假设 发育和炎症。特异性Aim 1将决定FBXO 11是否是成骨细胞所必需的。 通过使用FBXO 11过表达和敲低的成骨细胞培养物， 骨移植实验和条件性FBXO 11敲除小鼠模型。具体目标2将确定是否 FBXO 11/Snail 1/LSD 1调节轴有助于多微生物中的炎性骨重建 牙周炎和种植体周围炎动物。Specific Aim 3将确定我们是否可以将此FBXO 11轴渲染为 治疗牙周炎和种植体周围炎的新靶点， 世界各地。我们提出了两个创新的方法，基因治疗的基因工程FBXO 11 成骨细胞中的转基因和用特异性LSD 1抑制剂反式-2-苯基环丙胺进行局部干预 （2-PCPA），FDA批准的抗抑郁药物，以防止骨质流失和促进骨再生。 如果这项拟议的研究证实了我们的假设，即重新利用2-PCPA治疗炎症性骨病， 我们将考虑将2-PCPA用于治疗慢性牙周炎和种植体周围炎的应用推广到临床， 问题研究