基因间长非编码RNA-UC002yug.2调控成骨细胞功能及其在绝经后骨质疏松症中的作用机制

Long intergenic non-coding RNA (LincRNA) may regulate important signal transduction of human osteoblast (HOB) and be associated with onset of postmenopausal osteoporosis (PMOP). Our preliminary study has mined out 13 candidate lincRNAs from the chromosome regions reported to be related with high susceptibility to OP. Among them, lincRNA-UC002yug.2 was indicated to be overexpressed in PMOP HOB, which was related to the inhibitory function of HOB and thus may be involved in the pathogenesis of PMOP. Based on these preliminary results, we will use the technology of RNA interference to inhibit the expression of UC002yug.2 in vitro PMOP HOB and observe its influence towards PMOP HOB proliferation, differentiation and mineralization. Then we will apply the methods of expression profile microarray and RNA-binding protein immunoprecipitation (RIP) to find the targets related to the biological function of UC002yug.2. Moreover, we will adopt the technologies of gene transfection and RNA interference to intervene the expression of UC002yug.2 and its targets, which can achieve reproduction or blocking-up of the function of UC002yug.2, and revalidate the effect of UC002yug.2 on the HOB function and its mediation by the targets. In addition, with the collected clinical samples, we will analyze the correlation of the expression of UC002yug.2 and targets with PMOP and the association of UC002yug.2 genetic variation with PMOP. These results will provide new targets for the prevention and treatment of PMOP.

基因间长非编码RNA（LincRNA）可调控人成骨细胞（HOB)信号转导，与绝经后骨质疏松症（PMOP）发生相关。从前期挖掘到的OP高易感染色体区内的13个候选 LincRNA中，我们筛选出UC002yug.2在PMOP HOB的高表达，并发现其与PMOP HOB功能抑制有关，提示UC002yug.2可能影响HOB功能从而涉及PMOP发病机制。本项目拟采用 RNAi下调PMOP HOB UC002yug.2，观察其对PMOP HOB增殖、分化和矿化影响；通过表达谱芯片和RIP等实验，找到与UC002yug.2功能相关靶标；应用基因转染和RNAi干预UC002yug.2和靶标以实现UC002yug.2功能的再现或阻断，对其调控的HOB功能及靶标真正介导作用再验证；利用已征集的临床样本分析UC002yug.2和靶标的表达及UC002yug.2遗传变异与PMOP间关联，为PMOP防治提供新靶点。

基因间长非编码RNA（LincRNA）可调控人成骨细胞（HOB)信号转导，与绝经后骨质疏松症 （PMOP）发生相关。从前期挖掘到的OP高易感染色体区内的13个候选 LincRNA中，我们筛选出UC002yug.2在PMOP HOB的高表达，过表达LncRNA-UC002yug.2 抑制MG-63细胞增殖，下调OPG mRNA和蛋白水平，上调RANKL mRNA和蛋白水平，降低OPG/RANKL mRNA或蛋白比值；相反下调LncRNA-UC002yug.2表达可改善雌激素缺乏导致MG-63细胞增殖下降，上调OPG mRNA和蛋白水平，下调RANKLmRNA和蛋白水平，提高OPG/RANKL mRNA或蛋白比值。LncRNA-UC002yug.2在雌激素缺乏降低MG-63细胞增殖和OPG/RANKL mRNA或蛋白比值中发挥重要作用。UC002yug.2 rs2246640(C>T)与OP易感关联，rs2246640-T是原发性OP的风险等位基因。UC002yug.2 rs2246640、体重指数BMI、体力活动间交互作用与OP易感关联，低BMI、携带rs2246640-T等位基因以及体力活动下降是OP易感的风险因素。为PMOP防治防治新靶点提供依据。课题完成时发表标注SCI论文6篇，培养研究生4名。