Mechanisms of peroxisome proliferator-activated receptor-alpha regulation in peridontitis

过氧化物酶体增殖物激活受体-α在牙周炎中的调节机制

• 批准号: 10915090
• 负责人: Yang Hu
• 金额: $ 49.75万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-08 至 2024-09-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10915090
• 关键词: Agonist; Anti-Inflammatory Agents; Antigens; Binding; Bone Regeneration; Bone Resorption; CD36 gene; Cell Proliferation; Cells; Chronic; Competitive Binding; Complex; Data; Deterioration; Development; Disease; Disease model; Dissociation; Dose; Enhancers; Etiology; Fenofibrate; Future; Gene Expression; Genes; Genetic Transcription; Gingiva; Grant; Immune; In Vitro; Inflammation; Inflammatory; Interleukin-10; Jaw; Knockout Mice; Knowledge; Lipopolysaccharides; Macrophage; Mediating; Mission; Molecular; Mus; NF-kappa B; Nuclear; Nuclear Hormone Receptors; Osteolytic; Osteoporosis; PPAR alpha; PPAR gamma; PPAR-beta; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Periodontal Diseases; Periodontal Ligament; Periodontitis; Peroxisome Proliferator-Activated Receptors; Peroxisome Proliferators; Phenotype; Play; Prevention; Process; Public Health; Publications; Publishing; Regulation; Reporting; Research; Response Elements; Rheumatoid Arthritis; Risk; Role; Signal Transduction; Systemic disease; T cell activating factor; TCF7L2 gene; TNF gene; Therapeutic; Therapeutic Studies; Tissues; Tooth Loss; Transcription Coactivator; United States National Institutes of Health; Virulent; WNT Signaling Pathway; alveolar bone; beta catenin; bone; bone loss; cell type; cytokine; immunoregulation; in vivo; inhibitor; insight; microorganism; novel; novel therapeutic intervention; p65; periodontopathogen; protective effect; receptor function; response; transcription factor

Project Summary This application is for the extension of our current R03 grant titled “Pathogenic role of peroxisome proliferator- activated receptor alpha in periodontitis”, which has produced 2 published and 1 under review publications so far. Our studies have focused on the pathogenic role of PPARα in periodontal inflammation and bone resorption. Specifically, we demonstrated that PPARα not PPARβ or PPARγ had decreased expression levels in gingival cells stimulated with periodontitis antigens and in gingival tissue of mouse experimental periodontitis, and PPARα agonist treatment significantly reduces inflammation and bone loss in experimental periodontitis. While the mechanism of how activated PPARα regulates these pathology of periodontitis is largely unknown. Our recent data demonstrated that activation of PPARα inhibited the NF-kB (p65) signaling and increased the anti- inflammatory cytokines IL-10 and its secretion factor CD36 in the macrophages. The Wnt pathway was aberrantly activated in the macrophage during periodontitis in vivo and activated PPARα decreased Wnt/β-catinin/TCF-4 activity and induced a binding of β-catenin with PPARα in in vitro studies. Together with the previously published findings by others, we hypothesize that PPARα is an effective macrophage modulator through diversion the Wnt/β-catenin signaling via competing with TCF4 for binding to β-catenin, enhancing the CD36/IL-10 mediated anti-inflammatory transcriptional activities and suppressing the TCF4 mediated pro- inflammatory transcriptional activities. In this proposal, we will first determine if PPARα agonist’s periodontitis protective effect is via modulating macrophage polarization through a PPARα agonist dependent mechanism (Aim 1); Then we will explore the underlying mechanism by which PPARα modulates macrophage in the periodontitis (Aim 2). Successful completion of this project will generate conceptual advances in our understanding of the etiology of the disease by highlighting previously poorly understood pathways of inflammation. If our hypothesis is correct, these studies will broaden our insights into the potential role of PPARα in the regulation of macrophages in the inflammation of periodontal disease, as well as other immune-mediated osteolytic conditions such as osteoporosis or rheumatoid arthritis.

项目摘要 该应用是为了扩展我们当前的R03赠款，标题为“过氧化物组增殖剂的致病作用 - 激活的受体α在牙周炎中”，它已发表了2份，其中1个正在审查出版物中，因此 远的。我们的研究集中在PPARα在牙周感染和骨骼分辨率中的致病作用。 具体而言，我们证明了PPARα不是PPARβ或PPARγ的表达水平提高了牙龈水平 用牙周炎抗原和小鼠实验牙周炎的牙龈组织刺激的细胞，PPARα 激动剂治疗可显着降低实验牙周炎的感染和骨质流失。而 激活PPARα如何调节这些牙周炎病理学的机制在很大程度上尚不清楚。我们的最新消息 数据表明，PPARα的激活抑制了NF-KB（P65）信号，并增加了抗抗。 巨噬细胞中炎症性细胞因子IL-10及其分泌因子CD36。 Wnt途径异常 在体内牙周炎期间在巨噬细胞中激活并激活的PPARα降低了Wnt/β-catinin/tcf-4 活性并诱导β-catenin与PPARα在体外研究中的结合。以及先前出版的 其他人的发现，我们假设PPARα是通过转移的有效巨噬细胞调节剂 通过与TCF4竞争与β-catenin结合的Wnt/β-catenin信号传导，增强了CD36/IL-10 介导的抗炎转录活性并抑制TCF4介导 炎症转录活动。在此提案中，我们将首先确定PPARα激动剂是否牙周炎 保护作用是通过通过PPARα激动剂依赖机制调节巨噬细胞极化 （目标1）;然后，我们将探索PPARα调节巨噬细胞的潜在机制 牙周炎（AIM 2）。成功完成该项目将在我们的 通过强调以前了解的途径，了解疾病的病因 炎。如果我们的假设是正确的，这些研究将扩大我们对PPARα潜在作用的见解 在调节牙周疾病炎症中的巨噬细胞以及其他免疫介导的 骨质疏松症或类风湿关节炎，例如骨质疾病。