凝溶胶蛋白GSN介导雄激素受体抑制外周血单核细胞抗凋亡的作用机制研究

Peripheral blood monocytes (PBMs), as the functional target cells of androgens, are involved in the regulation mechanism of bone metabolism. Androgen promotes bone resorption inhibition caused by apoptosis of PBMs via binding androgen receptor (AR), but the specific mechanism remains unclear. Our previous studies found that, as a transcriptional co-activator of AR, the expression of Gelsolin (GSN) in Caucasian PBMs was significantly positively correlated with bone mineral density. Based on these studies, we used PBMs as the research object to analyze the effects of regulating androgen and AR activity on the downstream genes of the apoptosis pathway, and then observed the effects of regulating GSN expression on the AR activity, to explore the possibility of GSN-mediated AR regulating the anti-apoptosis pathway of PBMs. Furthermore, gene knockout technology was used to construct a zebrafish model with GSN mutation, to analyze the effects of androgen and AR activities on bone changes in zebrafish, and to preliminarily explore the molecular biological functions of GSN in bone metabolism regulation mechanism. This study will provide a theoretical basis for deepening the understanding of the molecular mechanism of PBMs anti-apoptosis and discovering new therapeutic targets for osteoporosis.

外周血单核细胞（PBMs）作为雄激素的功能靶细胞，参与骨代谢调节机制。雄激素通过结合雄激素受体（AR）促进PBMs细胞凋亡导致的骨吸收抑制，但具体作用机制仍不清楚。我们的前期研究发现，凝溶胶蛋白（GSN）作为AR的转录共激活因子，其在白人PBMs中的表达与骨密度显著地正相关。在此研究基础上，我们采用PBMs为研究对象，分析调节雄激素和AR活性对抗细胞凋亡通路下游基因的影响，然后观察调节GSN表达对AR活性的影响，探讨GSN介导AR调节PBMs抗凋亡通路的可能性。进一步利用基因敲除技术构建GSN突变的斑马鱼模型，分析调节雄激素和AR活性对斑马鱼骨骼变化的影响，初步探明GSN在骨代谢调节机制中的分子生物学功能。本研究将为加深对PBMs抗细胞凋亡分子机制的认知、发现新的骨质疏松症治疗靶标提供理论基础。

骨质疏松症（OP）是一种以全身骨密度（BMD）降低和骨组织微结构退化为特征的全身性骨骼疾病。OP的发病机制受遗传和环境因素共同控制，主要由于是负责骨吸收的破骨细胞比负责骨形成的成骨细胞更活跃所导致的。该项目研究发现，GSN基因的低表达减少了成熟破骨细胞的形成，并削弱其对骨骼的吸收降解功能，并导致骨骼发育异常。利用小鼠骨髓来源的原代巨噬细胞开展多时间点转录组分析，揭示GSN通过参与造血干细胞分化、蛋白消化吸收和矿物消化吸收等通路来调控破骨细胞的分化与成熟。通过整合基因组和转录组学数据，一个基因共表达模块被鉴定到与绝经后女性的BMD呈显著负相关。随着女性绝经发生的激素水平和代谢稳态改变，该模块内基因的表达谱而发生较为明显的变化，模块内核心基因TCF15被初步验证通过调控造血干细胞分化来参与骨代谢相关生物学活动。研究还从表观遗传学和转录组学水平评估了环境因素干扰内分泌对成年斑马鱼骨骼和性腺发育的影响及其分子机制，针对不同物种开展多组学水平的探索研究，为探究OP发病机制、寻找可靠治疗靶点提供新的思路。