不同病理类型氟骨症大鼠全基因组DNA甲基化谱分析及钙、蛋氨酸干预研究

地方性氟中毒是持续列入我国“十一五”、“十二五”、“十三五”和“健康中国2030规划纲要”的重点防治疾病。氟骨症病变复杂多样（骨硬化、骨质疏松和骨软化）并受营养因素影响。骨转换加速（骨形成与骨吸收平衡破坏）是氟骨症特征性病变，但现有机制学说并不能解释氟骨症复杂病理表现。本项目在既往发现p16、p21DNA甲基化参与氟中毒成骨细胞增殖活跃基础上，复制不同病理类型氟骨症大鼠模型，通过全基因组甲基化测序揭示氟骨症骨硬化、骨质疏松和骨软化病变中DNA甲基化谱的异同，筛选差异甲基化区域及差异甲基化基因；构建大鼠成骨和破骨细胞氟中毒模型，展开差异甲基化基因在骨形成和骨吸收过程中的功能研究；并在氟骨症大鼠中探索钙及蛋氨酸干预机制研究。其研究结果对揭示不同病理类型氟骨症发生机制具有重要的理论意义及学术价值，并为有针对性地应用营养素预防和治疗地方性氟中毒提供科学依据。

The endemic fluorosis has been listed in our country’s “11th Five-Year Plan”, the “12th Five-Year Plan”, the “13th Five-Year Plan” and the “Healthy China 2030 Action Plan” as an important prevented disease. The bone lesions in skeletal fluorosis are complex and diverse (osteosclerosis, osteoporosis and osteomalacia) and are affected by nutritional factors. Accelerated bone turnover ( bone formation and bone resorption were out of balance) is a characteristic lesion of skeletal fluorosis. However, the existing mechanism does not fully explain the complex pathological manifestations of skeletal fluorosis. Our previous studies found that DNA methylation of p16 and p21 was involved in osteoblast active proliferation induced by fluoride. In this study, the rat models of skeletal fluorosis with different pathological types are to be established. The similarities and differences of DNA methylation profile of osteosclerosis, osteoporosis and osteomalacia in skeletal fluorosis will be revealed using whole genome methylation sequencing, then the differentially methylated regions and related genes will be screened. Further, rat osteoblast and osteoclast models of fluorosis are to be established, and the functional studies of differentially methylated genes in processes of bone formation and resorption are to be conducted. The intervention mechanism of calcium and methionine are also to be explored in rats with skeletal fluorosis. The results would have important theoretical significance and academic values on revealing the pathogenesis of different pathological types of skeletal fluorosis, and would provide scientific basis for the prevention and therapy of endemic fluorosis with nutrient supplements.