NF-κB调控周期蛋白表达引起BPH上皮细胞衰老的机制研究

批准号：

82070777

项目类别：

面上项目

资助金额：

55.0 万元

负责人：

金杰

依托单位：

北京大学

学科分类：

前列腺及膀胱良性疾病

结题年份：

2024

批准年份：

2020

项目状态：

已结题

项目参与者：

金杰

关键词：

良性前列腺增生前列腺上皮细胞细胞周期蛋白细胞衰老 NF-κB通路

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结项摘要

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中文摘要

良性前列腺增生(BPH)是老年男性常见病，其发生发展被看作是机体老化的表现之一。细胞衰老是本质上不可逆的细胞生长周期停滞，BPH组织普遍存在缺氧环境和衰老的上皮细胞。我们前期发现，缺氧可激活NF-κB通路诱导上皮细胞衰老并促进其分泌衰老相关表型(SASP）IL-15，此过程与细胞周期蛋白(p21/p27)的改变相关。故假设：被缺氧激活的NF-κB通路对p21/p27进行表达调控引起上皮细胞衰老。本课题拟①分析缺氧诱导前列腺上皮细胞衰老时NF-κB信号通路的变化；②研究NF-κB对p21/p27表达调控作用；③分析BPH前列腺组织NF-κB通路蛋白、p21/p27及IL-15等表达分布情况；探究NF-κB通路与p21/p27的相互关系；④在衰老大鼠模型验证上述分子水平和病理研究结果。本课题拟阐明BPH上皮细胞衰老促进BPH的分子机制，为人们以新的视角认识BPH和临床BPH治疗提供理论依据。

英文摘要

Benign prostatic hyperplasia (BPH) is a common disease in elderly men, and its occurrence and development are considered as one of the signs of senescence. Cell senescence is an irreversible arrest of the cell cycle. Hypoxia microenvironment and senescent epithelial cells are very common in prostate tissues of BPH patients. In our previous studies it was found that hypoxia can induce cell senescence through the NF-κB pathway and the senescence cells secret the Senescence-Associated Secretory Phenotype (SASP)- IL-15, which is related to the upregulation of cell cycle-related cyclin (p21 and p27). Therefore, our hypothesis is that activated NF-κB pathway induces senescence of prostate epithelial cells and accelerates benign prostate hyperplasia via regulating cyclin expression (p21 and p27). In this project, at first, we will investigate the changes of NF-κB signaling pathway during the hypoxia-induced senescence of prostate epithelial cells; Then, we would explore the cyclin expression (p21 and p27) regulated by NF-κB pathway; Thirdly, in the prostate tissue of BPH patients we will analyze the expression and distribution of NF-κB pathway related proteins, p21/p27, and IL-15; Last, in aging rat model we would further verify the above results at tissue level and molecular levels. We intend to clarify the molecular mechanism of BPH epithelial cell senescence, which would broaden our horizon of understanding BPH pathogenesis and provide reliable theoretical basis for the BPH therapy.

良性前列腺增生（BPH）是一种常见的与年龄相关的泌尿系统疾病，特征是前列腺内衰老上皮细胞的积累。这些衰老细胞通过分泌衰老相关分泌表型（SASP）来促进BPH的发展。然而，缺氧诱导的细胞衰老在BPH中的分子机制尚不完全清楚。本研究通过激光捕获显微切割（LCM）和单细胞RNA测序（scRNA-seq）对人类BPH前列腺组织进行分析，发现衰老细胞中HIF-1α和衰老标志物（如p21、p27、Rb）表达显著上调。在体外实验中，使用CoCl2诱导的缺氧环境促进了细胞衰老并增加了SASP因子的表达，这一过程可以通过抑制HIF-1α得到逆转。进一步分析揭示了NF-κB信号通路的激活。小鼠BPH前列腺组织的单细胞RNA测序实验验证了上述结果。本研究表明，HIF-1α/NF-κB信号通路在缺氧诱导的BPH细胞衰老中发挥关键作用，为未来的治疗策略提供了潜在的靶点。