Pathogenic role of peroxisome proliferator-activated receptor alpha in periodontitis

项目摘要 牙周炎是美国成年人的一个重要公共卫生问题，付出了巨大的经济代价 预防和治疗，并对生活质量产生重大影响。不受控制的牙周炎会导致前- 紧张性牙齿脱落，颌骨退化，并增加发展系统性疾病的风险。常规 依赖抗生素和机械去除牙菌斑的治疗是暂时有效的， 它们间接地解决了牙周炎的炎症和相关免疫反应， 直接影响发病机制。因此，迫切需要研究新的靶分子， 直接调节牙周炎炎症和骨丢失的发病机制。已经证明 PPARα激动剂（PPARαA）是PPARα特异性的，具有强大的保护作用，可限制炎症， 自身免疫性疾病，调节炎症。我们的初步数据表明，一种过氧化物酶体增殖物激活受体αA，非诺贝特， 在实验性牙周炎小鼠模型中， 提示PPARα在牙周炎中的病理作用值得进一步研究。我们提出 目的：探讨过氧化物酶体增殖物激活受体α（PPAR α）在牙周炎中的作用。到 为此，提出了两个不同但互补的具体目标。Aim 1将决定PPARα而不是PPARβ 或过氧化物酶体增殖物激活受体γ（PPARγ）在牙周炎中表达水平的变化。目标2将确定PPARα敲除或过表达- 在实验性牙周炎小鼠模型中，锡永会影响炎症和骨丢失。的理解 研究Aim 1过程中牙周炎组织中PPARα表达水平的变化，为Aim 2过程中牙周炎组织中PPARα表达水平的变化提供依据。 本研究的目的是揭示PPARα在炎症调节和骨稳态调节中的作用， 牙周病在以往经验的基础上，目标1和目标2将导致 用于牙周炎和各种其他口腔疾病的新型PPARα靶向疗法。成功完成本 该项目将导致更好地了解PPARα在牙周炎中的分子和细胞作用，并将其转化为 这一知识，以开发一个应用系统，以实现持续释放与非侵入性局部交付， 牙周炎的临床治疗。

Project Summary Periodontitis is an important public health problem among adults in the U.S., with major economic costs for prevention and treatment and significant impact on quality of life. Un-controlled periodontitis can cause ex- tensive tooth loss, jaw bone deterioration, and increased risk of developing systemic diseases. Conventional treatments that rely on antibiotics and mechanical removal of dental plaque are transiently effective because they indirectly address the inflammation and related immune responses that underlie periodontitis, but do not directly impact pathogenesis. Thus, there is a compelling need to investigate novel target molecules which di- rectly modulate pathogenesis for both inflammation and bone loss in periodontitis. It has been demonstrated that PPARα agonists (PPARαA), which is PPARα specific, have robust protective actions limiting inflammation in autoimmune disease, modulating inflammation. Our preliminary data suggest that a PPARαA, fenofibrate, has the potential to reduce periodontal inflammation and bone resorption in experimental periodontitis mouse mod- els, suggesting that the pathological role of PPARα in periodontitis deserves further investigation. We propose to test the hypothesis that PPARα not PPARβ or PPARγ plays important pathological roles in periodontitis. To that end, two distinct but complementary specific aims are proposed. Aim1 will determine that PPARα not PPARβ or PPARγ has expression level changes in periodontitis. Aim 2 will determine PPARα Knockout or overexpres- sion will affect inflammation and bone loss in experimental periodontitis mouse model. The understanding of expression level change of PPARα in periodontitis investigated during Aim1 will provide the foundation for Aim2. The goal is to reveal the role of PPARα in inflammatory regulation and in modulation of bone homeostasis during periodontal diseases. Building on previous experience and both Aim1 and Aim2 will lead to the development of novel, PPARα targeted therapies for periodontits and various other oral diseases. Successful completion of this project will lead to better understanding of the molecular and cellular role of PPARα in periodontitis, and translate this knowledge to develop an application system to achieve sustained release with noninvasive local delivery for the clinical treatment of periodontitis.