PLS3基因通过骨基质蛋白代谢通路调控骨质疏松症的新机制及治疗新靶点的研究

随着我国老龄化进程加剧，骨质疏松症患病率急剧攀升，严重威胁人群健康。骨质疏松症受遗传和环境因素的复杂调控，但遗传调控机制尚未明。本课题组前期研究发现调控骨基质蛋白合成的重要基因PLS3突变可致母系遗传性骨质疏松症，我们得出科学假设：PLS3表达量下降，将导致重要骨基质蛋白Ⅰ型胶原的合成代谢缺陷，引起骨密度降低、骨折风险增加，这可能是骨质疏松症的重要发病机制。本课题将采用CRISPR/Cas9基因编辑技术，构建PLS3大片段缺失的新型骨质疏松大鼠模型，从分子、细胞、组织多层面深入研究PLS3突变对Ⅰ型胶原代谢及调控通路、骨转换、骨密度、骨微结构、骨生物力学性能的影响，并采用转染PLS3高表达质粒的骨髓间充质干细胞进行移植，探索分子靶向治疗对骨质疏松症的有效性。本研究对于揭示骨质疏松症的遗传调控新机制，探索新型干细胞靶向治疗的应用前景，具有重要意义。

With the progressive aging of Chinese population, the prevalence of osteoporosis is rapidly increasing, which has become a serious threat to people's health. Osteoporosis is complicatedly regulated by genetic and environmental factors, however, the genetic mechanism is unclear. In research of our group, we found that the mutation of PLS3, an important gene regulating the synthesis of bone matrix protein, could lead to maternal hereditary osteoporosis. We conclude a scientific hypothesis that the decrease of PLS3 expression would lead to the synthesis and metabolism defect of type I collagen, an important bone matrix protein, and lead to the decrease of bone mineral density and the increase of bone fracture risk, which could be the main mechanism of osteoporosis. To confirm this hypothesis, we will generate a novel rat model of osteoporosis with a large fragment deletion in PLS3 through CRISPR/Cas9 gene editing technology. The effects of PLS3 mutation on type I collagen metabolism and its signaling pathways, bone remodeling, bone mineral density, bone microstructure and bone biomechanical properties will be studied from the molecular, cellular and tissue levels. Then, bone marrow mesenchymal stem cells transfected with PLS3 high expression plasmid will be used for transplantation to the PLS3 knock-out rats, to explore the effectiveness of molecular targeted therapy in osteoporosis. This study is of great significance for revealing the new genetic mechanism of osteoporosis and exploring the application prospect of novel stem cell targeted therapy.