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

项目摘要 这个应用程序解决了问题9：“分子和/或细胞机制是什么？ 这是癌症治疗导致严重不良后遗症发展的基础吗？ 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(迷惑；记忆问题)，不能同时处理多项任务，智力受损 推理。而由中枢神经系统(CNS)指导的治疗(如放射和 鞘内化疗)是很容易理解的，潜在的关键和共同毒性的机制 在全身癌症治疗后，使用不直接针对大脑的药物进行化疗，包括 不清楚。来自系统治疗的CiCi风险患者的数量远远超过患者的数量 暴露于中枢神经系统治疗，但对系统治疗影响的机制知之甚少 CiCi，对于如何防止这种情况，目前还没有明确的愿景。我们之前已经展示了这一代人 细胞毒性化疗药物对活性氧的影响是脑损伤的重要介质 即使药物本身并没有进入大脑。还必须指出的是，抗癌药物， 专门针对具有特殊功能的癌细胞而设计，如Bcl2抑制剂家族，还 生成ROS。然而，靶向治疗对CiCi的影响从未得到解决，而且， 因此，他们的作用机制是完全未知的。这项提议的目标是测试整体 治疗诱导靶组织产生ROS导致循环肿瘤坏死因子α增加的假说 通过细胞外小泡(EVS)介导的反应，这种促炎细胞因子穿过血液 脑屏障可导致线粒体功能障碍和随后的神经元损伤，从而导致CiCi。以下是 特定的目的是检验ROS假说，了解EVS中介的 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 代表标准细胞毒性和实验性的化疗药物(多柔比星和万乃克莱) 淋巴瘤模型中的靶向药物。目标1将研究肿瘤坏死因子α在治疗诱导中的基础作用 神经元损伤以深入了解CiCi在脑内的作用机制并展示化疗的有效性 在氧化还原活性抗氧化剂存在的情况下。目标2将确定循环之间的机械联系 胞外小泡和治疗诱导的CiCi。目标3将确定肿瘤坏死因子α产生的起源细胞(S) 化疗会导致认知障碍。这些目标将在体外和体内使用 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，以及新型线粒体靶向抗氧化剂MNP，以改善CiCi而不降低其疗效 抗癌药物。该项目的结果将为未来的临床试验奠定重要的基础 改善接受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.