Hedgehog信号通路在颌骨骨纤维异常增殖症发病机制中作用的研究

Fibrous dysplasia (FD) is a skeletal disorder characterized by the replacement of normal bone and bone marrow with abnormal fibro-osseous tissues. FD affecting the jaws often involve multiple bones, and results in severe facial deformities and functional impairment. FD is thought to originate from the activating mutations of GNAS gene. However, the molecular mechanism of GNAS mutations contributing to FD pathogenesis remains poorly understood. Hedgehog (Hh) signaling pathway plays a critical role in the skeletal biology. Abnormality of this pathway has been implicated in numerous skeletal disorders, and modifying this pathway represents a promising therapeutic target for bone diseases. The role of Hh signaling in FD of jaw bones remains unclear. In this proposal, we will utilize a human sample bank of jaw bone FD to comprehensively study the role of Hh signaling in the pathogenesis of FD by combining histology, cellular and molecular biology and high throughput screening. Modifying Hh signaling as a potential treatment for FD will also be explored. The present proposal aims to provide further insights into the molecular pathogenesis of FD, and explore novel therapeutics for FD of the jaws by clarifying the role of Hh signaling pathway in the pathophysiology of this skeletal disorder.

骨纤维异常增殖症（Fibrous Dysplasia, FD）是一种正常骨被异常骨和纤维组织取代的骨纤维性病变。颌骨FD常累及颌面部多个骨，引起严重的面部畸形和功能受损。研究表明，颌骨FD的发生与GNAS基因突变有关，但其详细的分子发病机理尚不完全清楚，临床上亦无有效药物可阻止或逆转该病进展，是一亟待解决的临床难题。Hedgehog（Hh）信号通路在骨骼生物学中发挥着关键作用，其异常介导了多种骨疾病的发生，是临床重要的治疗靶点。本课题将在建立颌骨FD病人样品资源库的基础上，分离、鉴定GNAS突变与非突变细胞，在组织、细胞和分子等多水平系统研究Hh信号通路在颌骨FD发病机制中的作用，同时探索修饰该信号通路对该病的治疗潜能。本课题旨在通过阐明Hh信号通路在颌骨FD病理机制中的作用进一步促进对该病分子发病机制的理解，为寻找潜在的分子治疗靶标提供理论和实验依据。