基于cAMP-CREB1-HDAC8通路探讨BMSC在颌骨骨纤维异常增殖症中的发病机制

项目名称： 基于cAMP-CREB1-HDAC8通路探讨BMSC在颌骨骨纤维异常增殖症中的发病机制

项目编号： No.81500874

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 傅瑜

作者单位： 南京医科大学

项目金额： 18万元

中文摘要： 以骨髓基质细胞（BMSCs）成骨分化障碍及过度增殖为特征的颌骨骨纤维异常增殖症（FD）尚无有效的治愈方法，GNAS基因突变激活cAMP-CREB通路与其发病紧密相关。然而，该通路如何通过调控BMSCs成骨分化及增殖活性参与FD发病是有待解决的关键问题。我们前期研究发现：组蛋白去乙酰化酶8（HDAC8）抑制BMSCs成骨分化且在FD中高表达，CREB1与HDAC8启动子存在结合位点。本项目拟采用化学小分子干预、RNAi、染色质免疫沉淀等技术，分析cAMP-CREB1-HDAC8 通路调控BMSCs成骨分化、增殖活性及分子间功能关系；并探索抑制剂及HDAC8干扰在FD BMSCs裸鼠移植模型中抑制增殖、促进成骨分化、改善骨质结构的可行性和有效性。本研究不仅有助于深入认识FD的发病机制，而且有可能为临床治疗FD提供新思路。

中文关键词： 骨纤维异常增殖症；骨髓基质细胞；组蛋白去乙酰化酶8；成骨分化；增殖

英文摘要： The jaw fibrous dysplasia (FD) is characterized by osteogenic differentiation disorder and high proliferation activity of bone marrow stromal cells (BMSCs). There is still a lack of completed and effective therapy. cAMP-CREB pathway activated by GNAS gene mutation is closely associated with the onset of FD. However, the critical issue which remains to be solved is that how this pathway is involved in the pathogenesis of FD by regulating osteogenic differentiation and proliferation activity of BMSCs. Our previous studies have revealed that HDAC8 inhibits osteogenic differentiation of BMSCs by epigenetic regulation, importantly, higher HDAC8 is expressed in FD BMSCs compared to those healthy BMSCs. Moreover, there exist possible binding-site between CREB1 and the promoter of HDAC8 gene. In the present study, small chemical intervention, RNAi, ChIP are applied to analyze the osteogenic differentiation, proliferation activity and functional relationship between molecules of BMSCs regulated by cAMP-CREB1-HDAC8 pathway. The therapeutic effects of inhibitor and HDAC8 knockdown in nude mice models implanted with FD BMSCs are further determined to inhibit proliferation and promote osteogenesis, thus improving the bone microstructure. Our study will provide insights into the molecular regulation mechanism of FD development and progression, and offer novel clues to the clinical treatment of FD.

英文关键词： fibrous dysplasia;bone marrow stromal cells;HDAC8;osteogenic differentiation;proliferation