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

项目摘要 这项申请是我们目前的R03基金的延伸，该基金的标题是“过氧化物酶增殖物的致病作用-- 在牙周炎中激活受体α“，已经发表了2篇已发表的和1篇正在审查的出版物。 远远的。我们的研究主要集中在PPARα在牙周炎和骨吸收中的致病作用。 具体地说，我们证明了PPARα而不是PPARβ或PPARγ在牙龈中的表达水平降低 用牙周炎抗原刺激的小鼠牙周组织中的细胞和PPARα 激动剂治疗显著减少实验性牙周炎的炎症和骨丢失。而当 激活的PPARα如何调节这些牙周炎的病理机制在很大程度上还不清楚。我们最近 结果表明，PPARα的激活抑制了核因子-kB(P65)信号转导，增强了细胞免疫应答。 巨噬细胞炎性细胞因子IL-10及其分泌因子CD36Wnt通路异常 牙周炎时巨噬细胞的活化及活化的PPARα降低Wnt/β-Catinin/Tcf-4 体外研究表明，β-连环蛋白与PPARα具有结合活性。连同之前出版的 其他人的发现，我们假设PPARα是一种有效的巨噬细胞调节剂，通过分流 Wnt/β-连环蛋白信号通过与TCF4竞争结合β-连环蛋白，增强CD36/IL-10 介导的抗炎转录活性和抑制TCF4介导的促炎活性 炎性转录活动。在这项建议中，我们将首先确定PPARα激动剂的牙周炎 保护作用是通过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(目标2)。该项目的成功完成将在我们的 通过强调以前知之甚少的致病途径来理解疾病的病因 发炎。如果我们的假设是正确的，这些研究将拓宽我们对PPARα潜在作用的洞察力 巨噬细胞在牙周病炎症中的调控以及其他免疫介导作用 骨质疏松或类风湿性关节炎等溶骨性疾病。

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.