A novel bone-destructive pathway in periodontal disease

描述(申请人提供)：我们最近证明，共享表位(SE)通过作为配体激活促破骨细胞信号转导事件而参与类风湿性关节炎(RA)的发病。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-DRB1等位基因的关联，在这里，我们将检验这一基序可能通过其信号转导作用直接导致PD的骨损伤严重程度的假设。该研究计划有两个具体目标：特定目标1将使用一种新的小分子模拟SE化合物cQKRAA(包含一个共同的SE序列基序)来研究外源性添加的SE对帕金森病小鼠模型的影响。这种模拟SE的配体最近被证明在体外和体内都具有强大的促破骨细胞生成作用。在特定的目标2中，我们将使用表达带有SE序列的HLA-DR分子的转基因小鼠或对照SE阴性序列来检验内源性SE的影响。在初步研究中，SE转基因小鼠被发现具有增强的破骨细胞生成倾向。在这两个目标中，SE对帕金森病严重程度的影响的特异性将通过用一种新的特定的SE拮抗剂化合物来抑制来确定。因此，利用新的研究工具，拟议的研究将检验帕金森病发病机制的一个新概念。从长远来看，拟议的研究可能为未来的研究提供科学基础，为这种常见疾病开发新的治疗策略。

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.