胞内氯离子浓度对前列腺上皮细胞TLR4信号通路的调控机制研究

Chronic prostatitis is a common cause of male infertility disease. In the chronic inflammation, prostate epithelial cells showed the continuously activating of the TLR4/NF-κB pathway. Recently we firstly reported that CFTR, a chloride channel, act as initiative regulator and exert positive effects on the regulation of cell migration, cell juntion formation and cell maturation during skin wound healing process of mice (J Cell Physiol. 2015).In LPS induced NF-κB activation and inflammatory cell mode, we observed a new phenomenon,the intracellular [Cl-] increased after 4 hours of LPS treatment, and proved which are caused by CFTR decreasingly conducting the chloride. The results from preliminary experiments showed that the high [Cl-] can solely activated NF-κB pathway.But how CFTR is regulated to induce intracellular [Cl-] increased? and whether [Cl-] and NF-κB signaling pathway co-mediated the chronic inflammation is still unclear and need further study.Based on above results,we hypothesis that "in LPS treatment inflammatory mode,the increased intracellular [Cl-] and NF-κB signaling pathway form a positive feedback to sustain the continuously activation of NF-κB signaling as the inflammatory response of cell." To define the molecular mechanism about the intracellular [Cl-] increased and high [Cl-] positive feedback and activate the NF-κB signaling pathway, an integrative approach combining LPS inflammatory mode and modern electrophysiological methods, such as confocal measuring chlorine concentration will be undertook. Our experiment results will help us better to understand the mechanism for the development of chronic inflammation mediated by NF-κB→[Cl-]→NF-κB positive feedback loop, and potentially afford the new scientific strategy for the clinical treatment of chronic prostatitis.

慢性前列腺炎是男性不育的常见疾因,腺上皮细胞表现为TLR4/NF-κB炎症通路持续激活.我们最近在国际上首次发现氯离子通道CFTR对炎症修复过程中对角化形成细胞成熟分化有正向调节作用(J Cell Physiol.2015)。在LPS炎症激活NF-κB的细胞模型中，观察到胞内[Cl-]升高新现象，并证明是CFTR介导，预实验发现高[Cl-]可单独激活NF-κB。但CFTR如何被调控致胞内[Cl-]升高？[Cl-]和NF-κB信号通路是否共同介导慢性炎症尚不清楚。我们提出“LPS促进胞内[Cl-]升高后，高[Cl-]与NF-κB形成正反馈使炎症反应持续激活的假设”。拟采用LPS炎症模型和激光共聚焦测氯等现代电生理手段，探讨促[Cl-]升高、高[Cl-]反馈激活NF-κB通路的关键节点，阐释NF-κB→[Cl-]→NF-κB慢性炎症发展的机制，为临床治疗慢性前列腺炎的新策略提供科学依据。

慢性前列腺炎是男性不育的常见疾因，腺上皮细胞表现为TLR4/NF-κB炎症通路持续激活。我们最近在国际上首次发现氯离子通道CFTR对炎症修复过程中对角化形成细胞成熟分化有正向调节作用(J Cell Physiol.2015)。在LPS炎症激活NF-κB的细胞模型中，观察到胞内[Cl-]升高新现象，并证明是CFTR介导，预实验发现高[Cl-]可单独激活NF-κB。但CFTR如何被调控致胞内[Cl-]升高？[Cl-]和NF-κB信号通路是否共同介导慢性炎症尚不清楚。我们提出“LPS促进胞内[Cl-]升高后，高[Cl-]与NF-κB形成正反馈使炎症反应持续激活的假设”。我们采用LPS炎症模型和激光共聚焦测氯等现代电生理手段，证明了炎症模型中“NF-κB->PDE4->[Cl-]->SGK1->NF-κB正反馈作用环”的分子通路，并在多种炎症疾病中证明这个作用通路的存在。同时我们拓展了“炎癌”为中心的研究，包括研究NF-κB在[Cl-]介导的正反馈作用下的激活下靶基因的功能、炎症与代谢转化调控的相关研究、炎症与上皮细胞分化。最后获得以氯离子通路为中心的初步应用研究成果，筛选获得前列腺相关的氯离子通路及靶向联合抗肿瘤的成果，为临床治疗慢性前列腺炎和前列腺癌的新策略提供科学依据。