雌激素通过SOCS2抑制GH-IGF-1通路介导AGHD患者骨微结构改善疗效性别差异的机制研究

成人生长激素缺乏症（AGHD）患者接受重组人生长激素（rhGH）替代治疗的性别差异是本领域的难点。我们前期研究发现：(1)胰岛素样生长因子（IGF-1）是AGHD患者骨微结构受损的独立预测指标；(2)女性患者骨微结构改善差于男性，提示雌激素负调节GH/IGF-1通路。而SOCS2是肝脏GH/IGF-1通路的关键负调节因子。据此我们提出：雌激素通过抑制GH/IGF-1通路导致AGHD患者骨微结构改善的性别差异，SOCS2可能是关键分子。本项目拟通过临床队列研究，应用高分辨外周定量CT明确骨微结构改善的性别差异；应用基因敲除小鼠和RNA干扰技术，联合外周定量CT和骨计量学方法，从整体和细胞水平阐明雌激素通过SOCS2抑制GH/IGF-1通路介导AGHD患者骨微结构改善性别差异的机制。旨在揭示rhGH疗效性别差异的规律和分子机制，优化AGHD的临床诊疗方案，提升中国AGHD领域整体研究水平。

Gender differences in adult growth hormone deficiency (AGHD) patients receiving recombinant human growth hormone (rhGH) replacement therapy are difficult in this field. Our previous studies found that: (1) insulin-like growth factor (IGF-1) is an independent predictor of bone microstructural damage in AGHD patients; (2) the improvement of bone microstructures in female patients is worse than that in male patients, suggesting that estrogen negatively regulates GH/IGF-1 pathway. SOCS2 is a key negative regulator of GH/IGF-1 pathway in liver. Accordingly, we suggest that E2 leads to gender differences in bone microstructural improvement in AGHD patients by inhibiting GH/IGF-1 pathway, and SOCS2 may be a key molecule. This project intends to clarify the gender differences of bone microstructural improvement in AGHD patients through clinical cohort study, high resolution peripheral quantitative CT, gene knockout mice and RNA interference technology, combined with peripheral quantitative CT and bone metrology methods, to elucidate the mechanism of estrogen improving bone microstructural improvement in AGHD patients through inhibiting GH/IGF-1 pathway through SOCS2 at the overall and cellular level. The aim is to reveal the law and molecular mechanism of gender differences in the efficacy of rhGH, optimize the clinical diagnosis and treatment of AGHD, and enhance the overall level of research in the field of AGHD in China.