CD8+T细胞调控良性前列腺增生上皮细胞AR信号通路的作用及其分子机制研究

Benign prostatic hyperplasia (BPH) is one of the most common diseases in aging men, but the underlying mechanism is far from completely understanding. More and more evidence showed that inflammation could be a key component in BPH pathogenesis. CD8+ T cells are the mainly infiltrated inflammatory cells found in BPH prostate tissues. However, the consequences of CD8+ T cells towards prostate tissues remained unclear. Recently, we have shown that low intra-prostatic dihydrotestosterone (DHT) induced the BPH epithelial cells to recruit CD8+ T cells (data from 64 cases of BPH patients with/without androgen suppression treatment).Infiltrating CD8+ T cells could promote the proliferation of BPH epithelial cells, and this effect seems to be affected by androgen receptor (AR) signaling. Therefore, we hypothesized that infiltrating CD8+ T cells could promote the proliferation of prostate epithelial cells via AR signaling that is involved in the development and progression of BPH. In this project, we will investigate the following aspects:⑴Clinical study: in BPH patients, we will study the CD8+ T cells infiltration and functional status（proliferation/apoptosis）in prostate tissues; we will detect the difference of cytokines, AR and androgen responsive genes.⑵Cytology study：in the co-culture system between prostate epithelial cells (human primary prostate epithelial cells and prostate epithelial cell lines, respectively) and CD8+ T cells, we will study the influence of CD8+ T cells on the proliferation and apoptosis of prostate epithelial cells; and examine the change of cytokines in condition medium, AR and AR responsive genes on prostate epithelial cells.⑶Molecular mechanism research: by knocking-in AR and knocking-out AR in prostate epithelial cells, we will study the influence of the different cytokines on the proliferation and apoptosis of prostate epithelial cells to see which cytokines could impact on AR signaling and androgen responsive genes. We will illuminate the influence of CD8+ T cells on AR signaling in BPH pathogenesis.

良性前列腺增生(BPH)是老年男性常见疾病，免疫炎症参与BPH发生发展，但T细胞亚型对BPH的作用及机制尚不明确。我们前期发现，抗雄激素治疗后BPH前列腺上皮周围CD8+T细胞浸润增多；CD8+T细胞可促进前列腺上皮细胞增殖。故假设，CD8+T细胞通过调控上皮细胞雄激素受体(AR)信号通路促进BPH发生发展。本课题拟：⑴临床研究：研究BPH前列腺CD8+T细胞浸润与细胞因子、AR的关系；⑵细胞学研究：利用我们已建立的原代和BPH前列腺上皮细胞系，与CD8+T细胞共培养,研究CD8+T细胞对上皮细胞增殖/凋亡的影响，以及CD8+T细胞相关细胞因子和上皮细胞AR及雄激素相关基因的变化；⑶分子机制研究：加入或阻断差异细胞因子研究其对AR敲除和过表达的上皮细胞增殖/凋亡的影响，确定与AR形成信号通路的效应细胞因子及雄激素相关基因。本研究拟阐明CD8+T调控AR信号通路影响BPH发病的机制。