腹水非细胞成分来源肽PSPAP2提高卵巢癌紫杉醇敏感性的作用与机制研究

从卵巢癌患者腹水中探寻逆转化疗耐药新物质方兴未艾。前期申请人通过多肽组学筛选，发现一条在卵巢癌化疗敏感患者腹水非细胞成分中显著升高、功能未知的多肽PSPAP2；PSPAP2可提高卵巢癌细胞紫杉醇敏感性且不影响正常细胞；机制初探提示PSPAP2可结合自噬复合物蛋白ULK1并进一步抑制下游自噬。据此提出“腹水非细胞成分来源肽PSPAP2通过结合ULK1抑制自噬、从而提高卵巢癌紫杉醇敏感性”的假说。本研究拟从临床样本、细胞及动物水平全面评估PSPAP2促进卵巢癌紫杉醇敏感性的功能；采用分子物理学方法及哺乳动物单杂交等生物学技术、设计挽救实验阐明PSPAP2结合ULK1抑制自噬的分子机制；结合临床样本及动物模型验证PSPAP2/ULK1/自噬轴与卵巢癌紫杉醇敏感性的相关性。有关PSPAP2多肽在卵巢癌中的功能与机制未见报道，本研究如获成功，有望为逆转卵巢癌紫杉醇耐药提供新策略。

Ascites from ovarian cancer patients may contain substances which could reverse chemotherapy resistance to paclitaxel. In the preliminary study, a new peptide PAPAP2 which was significantly increased in the non-cellular components of ascites from chemosensitive ovarian cancer patientes was identified. PSPAP2 could improve the paclitaxel sensitivity of ovarian cancer cells without affecting normal ovarian cells. Further experiments suggested that PSPAP2 could bind to ULK1 and thus inhibit autophagy. Therefore, we propose the hypothesis that the ascites' non-cellular components derived peptide PSPAP2 improves the sensitivity of ovarian cancer to paclitaxel through binding ULK1 and inhibiting autophagy. In this study, the correlation between PSPAP2 and clinical data of ovarian cancer patients will be discussed. Moreover, we will deeply evaluate the function of PSPAP2 in promoting paclitaxel sensitivity by inhibiting autophagy using ovarian cancer cells and ovarian cancer orthotopic model. Then the interaction and relationship between PSPAP2 and ULK1 will be confirmed using physical methods, biological methods and rescue experiments.The function and mechanism of PSPAP2 in ovarian cancer is firstly reported by our study. If succeed, it is expected to provide a new strategy for reversing paclitaxel resistance in ovarian cancer.