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(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：
9363914
负责人：
SUBBARAO BONDADA
金额：
$ 45.51万
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 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9363914
关键词：
4 hydroxynonenal Address Alpha Cell 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 Family Functional disorder Future Generations Goals Immune Impaired cognition Impairment In Vitro Inflammatory Injury Intrathecal Chemotherapy Knockout Mice Link Lymphoma Magnetic Resonance Spectroscopy Mediating Mediator of activation protein Memory Mitochondria Modeling Molecular Mus Neuraxis Neuronal Injury Nitrates Oxidation-Reduction Oxidative Stress Pathology Patients Peripheral Permeability 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 antioxidant enzyme 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.

项目总结