(PQ9)A redox-mediated mechanism of chemotherapy-induced cognitive impairment

项目摘要 这个应用程序解决了挑衅性问题9：“什么是分子和/或细胞机制 导致癌症治疗引起的严重不良后遗症的潜在原因“聚焦于 化疗引起的认知障碍（CICI）。CICI现在是一种公认的毒性综合征，包括 执行功能丧失（混乱;记忆问题），无法进行多任务处理，智力受损 推理虽然CICI由中枢神经系统（CNS）定向治疗（例如放射和化疗）引起， 鞘内化疗）是容易理解的，潜在的机制是一个关键的和共享的毒性， 在使用不直接针对大脑的药物进行系统性癌症治疗后发生的化疗， 不清楚全身治疗导致CICI风险的患者数量远远超过 暴露于中枢神经系统治疗，但很少有人知道的机制介导的作用，全身治疗 CICI，并且对于如何预防这种情况没有明确的愿景。我们之前已经证明了这一代人 细胞毒性化疗药物引起的活性氧（ROS）是脑损伤的重要介质 尽管药物本身并没有进入大脑。还必须注意的是，抗癌药物， 专门设计用于靶向具有特定特征的癌细胞，例如Bcl 2抑制剂家族， 产生ROS。然而，靶向治疗对CICI的影响从未得到解决，并且， 因此，其作用机制完全未知。本提案的目标是测试 假设治疗诱导的ROS在靶组织中产生导致循环TNFα增加 通过细胞外囊泡（EV）介导的反应，这种促炎细胞因子穿过血液 脑屏障引起线粒体功能障碍和随后的神经元损伤，导致CICI。以下 具体的目的是为了测试ROS假设，了解EV介导的 机制，并使用两个原型在实验性癌症治疗环境中测试概念验证 化疗药物（阿霉素和维奈托克），代表标准的细胞毒性和实验 淋巴瘤模型中的靶向药物。目的1探讨肿瘤坏死因子α（TNFα）在治疗诱导的肿瘤细胞凋亡中的作用。 神经元损伤，以深入了解脑中CICI的机制并证明化疗的疗效 在氧化还原活性抗氧化剂的存在下。目标2将确定循环与 细胞外囊泡和治疗诱导的CICI。目的3将定义在肿瘤生长过程中产生TNFα的细胞来源。 化疗会导致认知障碍这些目标将在体外和体内实现， 国家的最先进的技术，包括磁共振光谱，氧化还原蛋白质组学，独特的动物 模型，和新的线粒体靶向抗氧化剂，MNP，以改善CICI，而不降低疗效， 抗癌药物。该项目的结果将为未来的临床试验奠定重要基础， 改善暴露于细胞毒性或靶向治疗的癌症患者的生活质量。

Project Summary This application addresses the Provocative Question 9: "What are the molecular and/or cellular mechanisms that underlie the development of cancer therapy-induced severe adverse sequelae?" focusing on Chemotherapy-induced cognitive impairments (CICI). CICI is now a recognized toxicity syndrome that includes loss of executive function (confusion; memory issues), inability to multitask, and impaired intellectual reasoning. While CICI caused by central nervous system (CNS)-directed therapies (such as radiation and intrathecal chemotherapy) is readily understood, the mechanisms underlying a critical and shared toxicity of chemotherapy that occurs after systemic cancer treatment with drugs that did not direct at the brain, are unclear. The number of patients at risk for CICI from systemic therapy far exceeds the number of patients exposed to CNS therapy, but little is known about the mechanisms mediating the effect of systemic therapy on CICI, and there is no clear vision of how to prevent this condition. We have previously shown that generation of reactive oxygen species (ROS) by cytotoxic chemotherapeutic drugs is an essential mediator of brain injury even though the drug itself did not get into the brain. It is also imperative to note that anticancer medications, designed specifically to target cancer cells with specialized features, such as the family of Bcl2 inhibitors, also generate ROS. However, the effect of targeted therapy on CICI has never been addressed, and, consequently, their mechanisms of action are entirely unknown. The goal of this proposal is to test the overall hypothesis that therapy-induced ROS production in the target tissues leads to increased circulating TNFα through extracellular vesicles (EVs)-mediated reactions, and this pro-inflammatory cytokine crosses the blood brain barrier to elicit mitochondrial dysfunction and consequent neuronal injury leading to CICI. The following specific aims are designed to test the ROS hypothesis, gain an understanding of the EVs-mediated mechanisms, and test the proof-of-concept in an experimental cancer therapy setting using two prototype chemotherapy agents (Doxorubicin and Venetoclax) that represent standard cytotoxic and experimental targeted drugs in a lymphoma model. Aim 1 will investigate the fundamental role of TNFα in therapy-induced neuronal injury to gain insights into mechanisms of CICI in the brain and demonstrate efficacy of chemotherapy in the presence of redox-active antioxidants. Aim 2 will determine the mechanistic links between circulating extracellular vesicles and therapy-induced CICI. Aim 3 will define the cell(s) of origin of TNFα produced during chemotherapy that leads to cognitive impairment. These aims will be accomplished in vitro and in vivo using state-of-the-art technologies, including magnetic resonance spectroscopy, redox proteomics, unique animal models, and novel mitochondria targeting anti-oxidant, MnP, to ameliorate CICI without reducing the efficacy of the anti-cancer drugs. The results from this project will lay important groundwork for future clinical trials to improve the quality of lives of cancer patients exposed to cytotoxic or targeted therapies.