A novel bone-destructive pathway in periodontal disease

描述（由申请人提供）：我们最近证明了共享表位（SE）通过作为激活促破骨细胞信号转导事件的配体参与类风湿关节炎（RA）的发病机制。考虑到RA和牙周病（PD）之间的关联，以及这两种疾病与编码SE基序的HLA-DRB1等位基因之间的关联，在这里，我们将研究SE基序可能由于其信号转导作用而直接导致PD骨损伤严重程度的假设。该研究计划有两个具体目标：具体目标1将使用一种新型的小SE模拟化合物cQKRAA来研究外源性添加SE对PD小鼠模型的影响，cQKRAA含有一个常见的SE序列基序。这种se -拟配体最近在体内和体外都显示出强大的促破骨作用。在Specific Aim 2中，我们将使用表达带有SE序列或对照SE阴性序列的HLA-DR分子的转基因小鼠来研究内源性SE的影响。在初步研究中，发现SE转基因小鼠具有增强的破骨倾向。在这两个目标中，SE对PD严重程度的特异性影响将通过一种新的特异性SE拮抗化合物抑制它来确定。因此，使用新的研究工具，提出的研究将探讨PD发病机制的新概念。从长远来看，本研究可以为未来研究开发新的治疗策略提供科学基础。

DESCRIPTION (provided by applicant): We have recently demonstrated that the shared epitope (SE) contributes to rheumatoid arthritis (RA) pathogenesis by acting as a ligand that activates pro-osteoclastogenic signal transduction events. Given the association between RA and periodontal disease (PD), and the association of both conditions with HLA-DRB1 alleles that code the SE motif, here we will examine the hypothesis that this motif may directly contribute to bone damage severity in PD due to its signal transduction effects. The research plan has 2 specific aims: Specific Aim 1 will examine the effect of an exogenously added SE in a mouse model of PD, using a novel small SE-mimetic compound, cQKRAA which contains a common SE sequence motif. This SE-mimetic ligand has been recently shown to have potent pro-osteoclastogenic effects in vitro and in vivo. In Specific Aim 2 we will examine the effect of endogenous SE, using transgenic mice expressing HLA-DR molecules with the SE sequence, or control SE-negative sequence. In preliminary studies, the SE transgenic mice were found to have enhanced osteoclastogenic propensity. In both aims, the specificity of the SE effects on the severity of PD will be determined by inhibiting it with a novel specific SE-antagonistic compound. Thus, using novel research tools, the proposed studies will examine a new concept in the pathogenesis of PD. In the long run, the proposed research could provide a scientific basis for future studies to develop new therapeutic strategies for this common disease.