共转录因子CITED1在甲状旁腺激素调控骨骼代谢中的机理研究

骨质疏松是一种目前机制不明的骨代谢失调疾病，现有预防治疗效果欠佳。甲状旁腺激素（PTH）是目前唯一证实可以通过增加骨量治疗骨质疏松的药物。生物信息学及部分实验证明共转录因子CITED1在PTH调节骨骼代谢中起到作用。本研究提出这一现象的机制假设：CITED1充当PTH成骨作用的负反馈抑制剂，抑制cAMP/PKA信号通路，PTH通过双重负向调节作用增加骨量。拟通过生物信息学和酵母双杂交技术筛选与CITED1结合的蛋白及其基因；从细胞层面上证实并分析CITED1对成骨平衡的调节作用；建立动物模型研究CITED1在间断小剂量PTH以成骨为主的调节及连续大剂量PTH以破骨为主的调节中的影响。通过研究PTH与CITED1在骨骼代谢中的交互作用，描绘相应的信号传导通路及模式调控机制图，揭示PTH在调节骨质沉积、增加骨量方面的作用。该研究将帮助理解骨骼代谢平衡，阐明PTH治疗骨质疏松机制并指导临床治疗。

Osteoporosis (OP) is one of the many bone metabolism disorders, which is a serious threat to all human health. The mechanism of the disease is not clear yet, therefore poor prevention and treatment effect still bother among population. Parathyroid hormone (PTH) is currently the only confirmed medicine which has curative effect against osteoporosis by increasing bone mass regulation. CITED1 is a transcription factor, which was found in previous studies involved in bone metabolism relative signal transduction. The mechanism, however, is not clear neither. Our previous study found that PTH can significantly promote the expression and function of CITED1. Furthermore, it is also found that CITED1 could contribute in the regulation of skeletal metabolism process through interaction with PTH pharmacology as well as its own inherent function. On the basis, this study aimed to screen out potential interactive proteins and corresponding genes with bioinformatic method and yeast double-hybrid technique, to confirm the effect of CITED1 on the balance of osteoblast/osteoclast system in the cells; and to establish animal models exploring the intermittent low-dose effect of promoting osteogenesis and the continuous large-dose effect of bone resorption. The pathway of signal transduction is going to be drawn with the description of CITED1 in its interactive effect with PTH as well as its inherent characteristics. Therefore the bone metabolism balancing and bone mass regulation effects of PTH are going to be further illuminated. This study will contribute in the understanding of mechanism and application of PTH in bone metabolism regulation and the management of osteoporosis.