组蛋白甲基转移酶NSD1调节骨发育与骨折修复的分子机制研究

Bone fracture is a common traumatic injury involving large organ, bringing serious influence to national health life. Repair of bone fracture is similar to early bone development. Although bone fracture can repair naturally in most cases, ten percent bone fracture can’t repair normally since the specific mechanism is unclear. Epigenetic regulation is closely related with bone growth, indicating that it may also play an important role in the process of bone fracture repair. Our previous study found that mesoderm mesenchymal stem cells specific knockout of H3K36 methyltransferase Nsd1 would cause defects to early bone development in mice, including apparently delay formed primary ossification center and secondary ossification center. With bone fracture model built, Nsd1 conditional knockout mice showed significantly delayed bone fracture repair. We propose to further study the phenotype of bone development and bone fracture repair in Nsd1 conditional knockout mice using X-Ray, CT scan and histochemistry analysis to understand the effects of NSD1 on bone development and fracture repair. With the method of biochemistry and molecular biology, combined with flow separation of fracture callus cells, we will further identify the important effector molecules regulated by NSD1 and H3K36 methylation, and elucidate the role and molecular mechanism of NSD1 in bone development and fracture repair. The project will help to understand the pathological mechanisms of bone fracture repair.

骨折是一种常见的累及大器官的创伤性损伤，给国民的健康生活带来了严重影响。骨折修复的过程类似于早期骨骼发育，通常骨折部位能够进行自我修复，但约有百分之十的骨折无法正常修复，具体机制尚不清楚。表观遗传调控与骨发育有着密切联系，提示表观遗传调控在骨折修复过程中也可能发挥着重要作用。我们前期研究发现，在中胚层间充质干细胞中特异性敲除组蛋白甲基转移酶NSD1，会导致小鼠早期骨发育缺陷，初级骨化中心与次级骨化中心的形成明显滞后，通过骨折模型的构建，发现Nsd1敲除小鼠骨折修复明显延迟。本项目拟利用X-Ray、CT扫描与组织化学等技术手段，进一步分析Nsd1基因对骨发育与骨折修复的影响。同时利用生物化学与分子生物学方法，结合骨痂细胞流式分选，鉴定NSD1以及组蛋白H3K36甲基化调控的重要效应分子，研究NSD1在骨发育与骨折修复过程中的作用及相关分子机制。本项目的实施将有助于对骨折修复分子机制的理解。