Sirtuin信号通路中Sirt5和SDHA蛋白预测卵巢癌卡铂化疗敏感性的流行病学及机制研究

卵巢癌在妇科恶性肿瘤中5年生存率最低，铂类化疗耐药是影响该疾病生存一个极其重要的原因，因此迫切需要寻找切实有效的策略来预测铂类化疗反应。我们前期通过基于卵巢癌预后队列的蛋白质组学研究发现，Sirtuin信号通路在卵巢癌卡铂耐药中发挥了重要作用；同时前期实验研究发现，该信号通路中Sirt5蛋白在卵巢癌卡铂耐药组中表达显著升高，与SDHA蛋白存在相互作用，但如何影响卡铂耐药的具体分子机制尚不清楚。本项目在前期工作基础上，拟运用分子、细胞、动物模型以及预后队列和机器学习等多种研究手段相结合，阐明Sirtuin信号通路中Sirt5和SDHA蛋白在卵巢癌卡铂耐药中的作用及分子调控机制；研究卵巢癌患者病理组织及外周血中Sirtuin和SDH蛋白家族表达对卡铂化疗敏感性的预测价值；构建并验证上述蛋白表达与肿瘤诊断后暴露因素相结合的卡铂化疗敏感性预测模型，旨在为改善卵巢癌卡铂耐药提供新的实验依据和策略。

Ovarian cancer has the lowest 5-year survival rate among gynecological malignant tumors. Platinum-based chemotherapy resistant is an extremely important factor affecting the survival of this disease. Therefore, it is urgent to find practical and effective strategy to predict the response of platinum chemotherapy. Our previous proteomic study, which based on the established ovarian cancer survival cohort, has demonstrated that Sirtuin signaling pathway play a key role in the carboplatin-based chemotherapy resistant. Meanwhile, results of our preliminary experiment indicated that compared to carboplatin sensitive group, the expression of Sirt 5 was significantly higher. There was an interaction between Sirt 5 and SDHA protein. However, the exact role and the regulation of molecular mechanism of Sirt 5 and SDHA protein in carboplatin resistant of ovarian cancer are not clear yet. On the basis of our previous work, our project will take advantage of multiple methods including molecular, cellular, and animal model as well as ovarian cancer survival cohort and machine learning. The objective of this project is to elucidate the role and the regulation of molecular mechanism of Sirt 5 and SDHA protein in carboplatin resistant of ovarian cancer; to explore the predictive role of Sirtuin and SDH family proteins expression in pathological tissues and peripheral blood of ovarian cancer patients for the sensitivity of carboplatin-based chemotherapy; to construct and validate the prediction model for the sensitivity of carboplatin-based chemotherapy combining the expression of the above proteins and post-diagnosis exposure. Hopefully, the novel experimental and theoretical foundation could be provided to improve the sensitivity of carboplatin-based chemotherapy of ovarian cancer patients.