雌激素受体GPER调节HIF-1α蛋白促进肌成纤维细胞表型转化参与BPH进展

良性前列腺增生BPH是老年男性常见进展性疾病，雌激素可促进前列腺间质增生，是BPH进展的重要因素。我们前期发现，早期进展BPH患者前列腺呈纤维样改变，雌激素受体GPER表达增高，GPER激动剂可促进肌成纤维细胞表型转化、分泌胶原纤维，并上调肌成纤维细胞表型转化关键分子—缺氧诱导因子HIF-1α。故假设：雌激素通过GPER调节HIF-1α，进而调控表型转化相关靶基因，促进肌成纤维细胞表型转化，加速BPH进展。本课题拟①分析不同进展阶段BPH患者前列腺内雌激素水平、GPER及HIF-1α等分子的表达；②明确GPER、HIF-1α促进肌成纤维细胞表型转化的作用；③探究GPER调控HIF-1α蛋白表达及HIF-1α调节肌成纤维细胞表型转化关键靶基因的分子机制。本课题拟阐明GPER调控HIF-1α促进肌成纤维细胞表型转化在BPH进展中的作用机制，为临床控制BPH进展提供理论依据。

Benign Prostate Hyperplasia (BPH) is one of most common progressive diseases among aging man. Estrogen has been recognized as one of the most important factors that may influence BPH progression by promoting the proliferation of mesenchymal cells. Recently, fibrosis-like alteration and higher expression of G protein-coupled estrogen receptor (GPER), a newly discovered transmembrane estrogen receptor, were detected in the prostate tissues of early-onset symptomatic BPH patients. Meanwhile the agonist of GPER could induce myofibroblast differentiation of fibroblast and upregulate the protein level of Hypoxia Inducible Factor-1α (HIF-1α). HIF-1α is a key molecular that may regulate myofibroblast-differentiation-related genes. Therefore, we hypothesized that estrogen could activate GPER to aler HIF-1α protein modification. Then HIF-1α may regulate other differentiation related genes and induce myofibroblast differentiation to promote BPH progression. In this project, first, we will analyze the concentration of estrogen and the expression of GPER, HIF-1α in the prostate of BPH patients with different progression stages. Then, we would verify the impacts of GPER and HIF-1α on myofibroblast differentiation of prostate fibroblast. Last, we may investigate the mechanism that GPER regulate HIF-1α protein modification and HIF-1α regulate differentiation related genes. The project will illustrate the role of GPER and HIF-1α in the myofibroblast differentiation of prostate fibroblast and the detailed mechanism. It might provide a theoretical basis of dealing with BPH progression.