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p27上调PHLPP1改善卵巢癌铂耐药的机制研究
结题报告
批准号:
82002771
项目类别:
青年科学基金项目
资助金额:
24.0 万元
负责人:
彭明刚
依托单位:
学科分类:
肿瘤治疗抵抗
结题年份:
2023
批准年份:
2020
项目状态:
已结题
项目参与者:
彭明刚
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中文摘要
卵巢癌化疗耐药是造成其五年生存率低下的最主要原因。p27是我们熟知的细胞周期相关蛋白,大量研究报道证实,p27在卵巢癌中低表达,并且参与了卵巢癌耐药,显著影响卵巢癌患者的生存期,但其具体的机制尚不清楚。PHLPP1是蛋白磷酸酶PP2C家族的一员,参与调控AKT,PKC等肿瘤耐药相关信号通路,但其在卵巢癌中的作用未见报道。我们的前期研究结果证实,p27可以正向调控PHLPP1表达,而后者可以直接调控AKT耐药通路。因此,我们提出p27能够促进PHLPP1表达进而改善卵巢癌铂耐药这一假说,并从以下三个方面展开验证:1.组织水平上验证PHLPP1与卵巢癌耐药的关系;2.细胞水平改变PHLPP1表达,检测卵巢癌细胞耐药性的改变;3.在体水平验证前期实验结果。本项目通过探索PHLPP1在卵巢癌耐药过程中的重要生理作用,旨在为卵巢癌化疗耐药提供新的理论基础和潜在治疗靶点,改善耐药型卵巢癌患者预后。
英文摘要
Chemotherapy resistance of ovarian cancer is the most important reason for the low Five-year survival rate. p27 is a well-known cyclin-dependent kinase inhibitor, which is identified by numerous studies that it is lowly expressed in ovarian cancer and participates in the process of ovarian cancer chemo-resistance,affecting patients' survival, but the mechanism is not totally understood. PHLPP1 is a novel member of the protein phosphatase 2C group, regulating AKT,PKC and other signaling pathways that relates to tumor drug resistance, while its function in ovarian cancer is totally unknown. Our recent studies found that p27 positively modulated PHLPP1 expression, while PHLPP1 could dephosphorylate AKT pathway directly .Therefore, we propose the hypothesis that p27 may promote PHLPP1 expression and improve platinum-resistance of ovarian cancer, which is verified by the following steps: 1. To confirm the relationship of PHLPP1 and ovarian cancer chemoresistance in cancer tissues; 2.To detect the changes of chemoresistance of ovarian cancer cells in vitro by altering the PHLPP1 expression; 3.To test the results in vivo. This study was designed to provide a new theoretical basis and treatment targets for ovarian cancer through exploring PHLPP1's role in ovarian cancer chemo-resistance and improve the prognosis of patients who are suffering from it.
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