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

(PQ9)化疗引起的认知障碍的氧化还原介导机制

基本信息

批准号：
10216188
负责人：
SUBBARAO BONDADA
金额：
$ 49.23万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10216188
关键词：
4 hydroxynonenal Address Animal Model Antibodies Antineoplastic Agents Antioxidants Apoptotic BCL2 gene Biochemical Blood - brain barrier anatomy Blood Circulation Brain Brain Injuries Cancer Patient Cancer Survivor Cells Choline Clinical Clinical Trials Cognition Confusion Cytotoxic Chemotherapy Development Doxorubicin Drug Targeting Drug usage Etiology Exposure to Family Functional disorder Future Generations Goals Immune Impaired cognition Impairment In Vitro Inflammatory Injury Intrathecal Chemotherapy Knockout Mice Link Lymphoma Lymphoma cell Magnetic Resonance Spectroscopy Mediating Mediator of activation protein Memory Mitochondria Modeling Molecular Mus Neuraxis Neuronal Injury Oxidation-Reduction Oxidative Stress Pathology Patients Peripheral Pharmaceutical Preparations Plasma Prevention Production Proteins Proteomics Publishing Quality of life Radiation Reaction Reactive Oxygen Species Recommendation Research Respiration Risk Role SOD2 gene Symptoms Syndrome Systemic Therapy TNF gene Technology Testing Therapeutic Effect Therapeutic Uses Tissues Toxic effect Toxicity due to chemotherapy Treatment Efficacy United States Vision anti-cancer antioxidant enzyme blood-brain barrier permeabilization cancer cell cancer therapy chemobrain chemotherapy cytokine cytotoxic design executive function experience extracellular vesicles improved in vivo inhibitor/antagonist insight macrophage mimetics mitochondrial dysfunction multitask neuron loss nitration novel prevent prototype specific biomarkers targeted treatment tumor

项目摘要

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.

项目摘要该应用程序解决了挑衅性问题9：“分子和/或细胞机制是什么这是癌症治疗引起的严重不良后遗症的发展？化学疗法引起的认知障碍（CICI）。 CICI现在是一种公认的毒性综合征，包括执行功能的丧失（混乱；记忆问题），无能为力和智力受损推理。而CICI由中枢神经系统（CNS）导向疗法（例如辐射和鞘内化疗）很容易理解在全身性癌症治疗未直接在大脑的药物治疗后发生的化学疗法是不清楚。有系统治疗的CICI风险的患者人数远远超过患者的数量暴露于中枢神经系统疗法，但对介导全身治疗对的机制知之甚少 CICI，并且没有明确的愿景，即如何防止这种情况。我们以前已经表明了这一代通过细胞毒性化学治疗药物的活性氧（ROS）是脑损伤的重要介体即使药物本身没有进入大脑。还必须注意，抗癌药物，专门针对具有专门特征的癌细胞，例如BCL2抑制剂家族产生ros。但是，靶向疗法对CICI的影响从未得到解决，并且，因此，他们的作用机制是完全未知的。该提议的目的是测试总体假设治疗诱导目标时间中的ROS产生会导致循环TNFα增加通过细胞外蔬菜（EVS）介导的反应，这种促炎性细胞因子越过血液脑屏障引起线粒体功能障碍，并导致CICI的神经元损伤。下列具体目的旨在测试ROS假设，了解EVS介导的机制，并使用两个原型测试实验性癌症治疗的概念验证代表标准细胞毒性和实验的化学疗法剂（阿霉素和维特诺卡克斯）淋巴瘤模型中的靶向药物。 AIM 1将研究TNFα在治疗诱导的神经元损伤以洞悉大脑中CICI机制并证明化学疗法的效率在存在氧化还原活性抗氧化剂的情况下。 AIM 2将确定循环之间的机械联系细胞外蔬菜和治疗引起的CICI。 AIM 3将定义在导致认知障碍的化学疗法。这些目标将在体外和体内实现最先进的技术，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型线粒体靶向抗氧化剂MNP，以改善CICI，而无需降低抗癌药。该项目的结果将为将来的临床试验奠定重要的基础提高暴露于细胞毒性或靶向疗法的癌症患者的生活质量。