MnBuOE as a Novel Chemosensitizer for Breast Cancer and Neuroprotector

MnBuOE 作为乳腺癌的新型化学增敏剂和神经保护剂

基本信息

批准号：
10189326
负责人：
Antino Recio Allen
金额：
$ 41.69万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10189326
关键词：
Address Adjuvant Therapy Affect Aftercare American Animal Model Animals Anti-Inflammatory Agents Antioxidants Apoptosis Architecture Behavioral Biochemistry Bioenergetics Blood - brain barrier anatomy Brain Brain Injuries Breast Cancer Model Breast Cancer Treatment Cancer Survivor Cell Respiration Cells Chemotherapy and/or radiation Clinical Cognitive Cognitive deficits Complication Confusion Cyclophosphamide Development Diagnosis Disease Distress Doxorubicin Equilibrium Event Functional disorder Genes Homeostasis Hydrogen Peroxide Impaired cognition Impairment Individual Inflammation Inflammatory Response Injury Intervention Knock-out Knowledge Lead Life Experience Maintenance Malignant Neoplasms Manganese Measures Mediating Memory impairment Metabolic Metastatic breast cancer Mitochondria Modeling Morphology National Cancer Institute Neuraxis Neuronal Differentiation Neurons Normal Cell Normal tissue morphology Nuclear Organ Oxidation-Reduction Oxidative Stress Oxygen Consumption Paclitaxel Pathogenesis Patients Performance Peripheral Personal Satisfaction Pharmaceutical Preparations Pharmacology Play Porphyrins Predisposition Production Promoter Regions Quality of life Reactive Oxygen Species Recording of previous events Regimen Reporting Research Research Personnel Response Elements Rodent Model Role SOD2 gene Superoxides Survival Rate Survivors Symptoms Testing Time Tumor Biology Tumor Tissue Tumor-Derived Up-Regulation Woman brain tissue cancer cell cancer diagnosis cancer therapy cell injury chemobrain chemosensitizing agent chemotherapy cognitive function cognitive performance combat cytotoxicity effective therapy functional independence improved insight malignant breast neoplasm mimetics mitochondrial dysfunction mouse model novel overexpression prevent protective effect radiation-induced tissue damage tumor tumor growth

项目摘要

Project Summary Background: The cognitive deficits observed after treatment with chemotherapeutic drugs are a significant clinical problem, with a rapidly increasing impact on the quality of life of millions of Americans. One and a half million people are diagnosed with cancer every year in the US, and more than 60% survive for 20 years or more. Cancer survivors have long reported cognitive dysfunction at various stages of the disease course with associated consequences upon well-being and functional independence. Several studies conducted over the past decade have indicated that cognitive impairment occurs long before cancer treatment begins and even before cancer diagnosis. Despite collective evidence for cognitive problems, far less is known about how tumor biology and cancer treatments can interact to lead to changes in the brain. The present study will use an orthotopic mouse model of breast cancer to delineate the effects chemotherapy on cognitive function. Moreover, we will test whether a novel antioxidant is capable of preventing the development of chemo/tumor- induced cognitive dysfunction. Hypothesis: We hypothesize that oxidative stress induced by chemotherapy treatment leads to changes in neuronal architecture and mitochondrial function impairing cognition which will be rescued by MnBuOE. Furthermore, Nrf2 function is critical for supporting neuronal maintenance after chemotherapy when aberrant ROS production is known to be exacerbated. Specific Aim 1: Determine if pharmacological upregulation of Nrf2 by MnBuOE protects the brain from chemotherapy induced injury. Aim 1.1) We will use a knockout model to determine if Nrf2 contributes to the protective effect of MnBuOE toward AC-T-induced brain injury. Aim 1.2) Determine if impaired Nrf2 expression plays a critical role in the pathogenesis of chemotherapy- induced brain injury. Specific Aim 2: Characterize the behavioral, neuroanatomical and morphological changes due to chemotherapy and the remediating effects of MnBuOE in a syngeneic model. Aim 2.1) Characterize mitochondrial bioenergetic changes in the brain associated with tumor ± chemotherapy and the effects of MnBuOE treatment. Specific Aim 3: Assess the influence of MnBuOE on tumor growth and susceptibility to chemotherapy (AC-T) in a patient derived tumor bearing animal model

项目概要背景：化疗药物治疗后观察到的认知缺陷是一个重要的因素。临床问题，对数百万美国人的生活质量的影响迅速增加。美国每年有 100 万人被诊断患有癌症，其中超过 60% 的人可以存活 20 年或癌症幸存者长期以来一直报告在病程的各个阶段存在认知功能障碍。对健康和功能独立性的相关影响进行了多项研究。过去十年的研究表明，损伤早在癌症治疗开始之前就已经发生，甚至尽管有大量证据表明存在认知问题，但人们对肿瘤如何发生知之甚少。生物学和癌症治疗可以相互作用，导致大脑发生变化。乳腺癌原位小鼠模型，用于描述化疗对认知功能的影响。此外，我们将测试一种新型抗氧化剂是否能够预防化疗/肿瘤的发展诱发认知功能障碍。假设：我们认为化疗引起的氧化应激会导致神经结构和线粒体功能损害认知，MnBuOE 可以挽救这种情况。此外，当异常时，Nrf2 功能对于支持化疗后神经元的维持至关重要众所周知，ROS 的产生会加剧。具体目标 1：确定 MnBuOE 对 Nrf2 的药理学上调是否可以保护大脑免受化疗引起的损伤。目标 1.1) 我们将使用敲除模型来确定 Nrf2 是否有助于 MnBuOE 的保护作用 AC-T 引起的脑损伤。目标 1.2) 确定 Nrf2 表达受损是否在化疗的发病机制中发挥关键作用 - 诱发脑损伤。具体目标 2：描述由于以下因素导致的行为、神经解剖学和形态学变化：化疗和 MnBuOE 在同基因模型中的修复作用。目标 2.1) 表征大脑中与肿瘤相关的线粒体生物能变化 ± 化疗和 MnBuOE 治疗的效果。具体目标 3：评估 MnBuOE 对肿瘤生长和化疗敏感性的影响 (AC-T) 在患者衍生的荷瘤动物模型中