A novel bone-destructive pathway in periodontal disease

描述（由申请人提供）：我们最近已经证明，共享表位（SE）通过作为激活促破骨细胞生成信号转导事件的配体而促进类风湿性关节炎（RA）发病。鉴于RA和牙周病（PD）之间的关联，以及这两种情况与编码SE基序的HLA-DRB 1等位基因的关联，在这里，我们将研究这一基序可能直接导致PD中骨损伤严重程度的假设，由于其信号转导作用。该研究计划有2个具体目标：具体目标1将使用含有共同SE序列基序的新型小SE模拟化合物cQKRAA，在PD小鼠模型中检查外源性添加SE的效果。这种SE-模拟配体最近已被证明在体外和体内具有强效的促破骨细胞生成作用。在具体目标2中，我们将使用表达具有SE序列或对照SE阴性序列的HLA-DR分子的转基因小鼠来检查内源性SE的作用。在初步研究中，发现SE转基因小鼠具有增强的破骨细胞生成倾向。在这两个目标中，SE对PD严重程度影响的特异性将通过用新型特异性SE拮抗化合物抑制PD来确定。因此，使用新的研究工具，拟议的研究将检查PD发病机制的新概念。从长远来看，拟议的研究可以为未来的研究提供科学依据，以开发这种常见疾病的新治疗策略。

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.