女性骨质疏松症新易感基因HERC2的分子遗传效应和基因功能的研究

Osteoporosis is an important global public health problem. Especially, it is the most serious disease threatening female health. Based on the previous study in which we found a new osteoporosis susceptibility gene HERC2 in female Caucasians, and combined with the latest international research that HERC2 gene encodes E3 ubiquitin ligase which affects bone turnover significantly, we suggest that HERC2 gene may be the risk gene that affects the stability of estrogen receptor which is at the key site in estrogen endocrine pathway in bone metabolism. This suggestion might be a breakthrough to find the relationship between HERC2 gene and estrogen receptor in female osteoporosis. In this study, we will use genotyping, exon sequencing and association analysis to find genetic effects of HERC2 gene in female osteoporosis. Also, we will adopt RNA interference to detect the function of HERC2 gene which would affect the expression of estrogen receptor and molecular pathogenesis of osteoporosis. The study is expected to determine the relationship between HERC2 gene and osteoporosis in Chinese female population, and to find the possible mechanism of HERC2 gene in estrogenic endocrine pathway. The results of this study will help researchers reveal the molecular pathogenic mechanism of female osteoporosis, and supply clinical guidance for hormone replacement therapy and SERM in treating osteoporosis. Moreover, it might be applied in early prediction of osteoporosis, as well as provide new ideas and scientific basis in the process of design for new medicines.

骨质疏松症是全球重要的公众健康问题，更是威胁女性健康的最严重疾病。本项目基于申请人在白人女性中发现骨质疏松症新易感基因HERC2的工作基础，结合国际最新发现HERC2基因编码的E3泛素连接酶对骨转换起着重要影响的研究结果，选择影响骨代谢中雌激素内分泌通路的雌激素受体在细胞中稳定性的风险基因为突破口，采用基因分型技术、外显子测序技术和关联分析方法，进行HERC2基因对女性骨质疏松症产生的分子遗传学效应的研究，并通过RNA干扰技术检测HERC2基因对雌激素受体表达的影响及其在骨质疏松症分子致病机理中的功能。本研究的完成可望确定HERC2基因与中国女性骨质疏松症的关系，阐明HERC2基因在雌激素内分泌通路中的作用机制，为进一步揭示女性骨质疏松症的分子致病机理、临床指导激素替代疗法和SERM的使用、骨质疏松症的早期预测诊断以及新药物的设计提供新思路和科学依据。