The Metabolic Basis of Cancer-Related Fatigue

癌症相关疲劳的代谢基础

基本信息

批准号：
9817128
负责人：
Robert Dantzer
金额：
$ 42.3万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-19 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9817128
关键词：
Affect Aftercare Attenuated Behavior Behavioral Biological Brain CASP1 gene CSF1 gene Cancer Model Cancer Patient Cell Nucleus Cells Cisplatin Cognitive Counseling Cytosol DNA Development Diagnosis Distress Education Emotional Energy Metabolism FDA approved Fatigue Genetic Gluconeogenesis Glycolysis Head and Neck Cancer Human Papillomavirus Immune Immune signaling Impairment Incidence Inflammasome Inflammation Inflammation Mediators Inflammatory Investigation Lewis Lung Carcinoma Liver Maintenance Malignant - descriptor Malignant Neoplasms Measures Mediating Metabolic Metabolic Pathway Mitochondria Modeling Motivation Mus Nature Neuraxis Neurosecretory Systems Organ Organism Oxidative Phosphorylation Passive Immunization Pathway interactions Patients Peripheral Phenotype Physical activity Process Proliferating Radiation therapy Reporting Research Research Project Grants Running Self Management Severities Signaling Molecule Skeletal Muscle Symptoms Syndrome Taxes Testing Time Tissues Warburg Effect Withholding Treatment Work aerobic glycolysis base behavior measurement cancer cachexia cancer cell cancer therapy chemotherapy common symptom curative treatments exhaustion experience irradiation metabolic phenotype mitochondrial dysfunction motivated behavior mouse model neoplastic cell novel pre-clinical prevent receptor response sensor tumor tumor growth tumor metabolism tumor progression willingness

Affect Aftercare Attenuated Behavior Behavioral Biological Brain CASP1 gene CSF1 gene Cancer Model Cancer Patient Cell Nucleus Cells Cisplatin Cognitive Counseling Cytosol DNA Development Diagnosis Distress Education Emotional Energy Metabolism FDA approved Fatigue Genetic Gluconeogenesis Glycolysis Head and Neck Cancer Human Papillomavirus Immune Immune signaling Impairment Incidence Inflammasome Inflammation Inflammation Mediators Inflammatory Investigation Lewis Lung Carcinoma Liver Maintenance Malignant - descriptor Malignant Neoplasms Measures Mediating Metabolic Metabolic Pathway Mitochondria Modeling Motivation Mus Nature Neuraxis Neurosecretory Systems Organ Organism Oxidative Phosphorylation Passive Immunization Pathway interactions Patients Peripheral Phenotype Physical activity Process Proliferating Radiation therapy Reporting Research Research Project Grants Running Self Management Severities Signaling Molecule Skeletal Muscle Symptoms Syndrome Taxes Testing Time Tissues Warburg Effect Withholding Treatment Work aerobic glycolysis base behavior measurement cancer cachexia cancer cell cancer therapy chemotherapy common symptom curative treatments exhaustion experience irradiation metabolic phenotype mitochondrial dysfunction motivated behavior mouse model neoplastic cell novel pre-clinical prevent receptor response sensor tumor tumor growth tumor metabolism tumor progression willingness

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项目摘要

Project Summary – Cancer-related fatigue is one of the most common and disruptive symptoms experienced by patients. It is often present at the time of diagnosis, worsens throughout treatment, and persists well after the cessation of treatment in a significant proportion of patients. The specific mechanisms responsible for fatigue remain largely unknown. Consequently, there are no mechanism-guided therapies for fatigue and the primary approach to patients reporting severe fatigue is education and counseling in the self-management of fatigue. Although conservation of energy is an important strategy in the management of fatigue, the possibility that cancer-related fatigue originates from alterations in energy metabolism has not been examined. The present project fills this void. Our working hypothesis is that cancer-related fatigue is the behavioral consequence of the excess metabolic demand imposed on the organism by the tumor and the inflammation it is possibly associated with. The relative metabolic inefficiency that results from this condition is worsened by the mitochondrial impairment that develops in peripheral tissues and the brain in response to chemotherapy and radiotherapy. To test our hypothesis, we will use two syngeneic murine models of cancer that both respond to a combination of cisplatin and local irradiation, a non-inflammatory model mimicking human papilloma virus-related head and neck cancer, and an inflammatory model represented by Lewis lung carcinoma. We will measure behavioral fatigue in both conditions by decreased voluntary wheel running and alterations in motivated behavior to account for the motivational component of fatigue. In Aim 1, we will determine whether inflammation associated with the tumor and its treatment needs to propagate to the brain for fatigue to develop. This will be done by comparing the time course of inflammation at the periphery and in the brain to that of fatigue before intervening to either block immune signaling molecules by passive immunization or deplete the innate immune cells that mediate the inflammatory process at the periphery and in the brain. In Aim 2, we will test the hypothesis that metabolic reprogramming by cancer and inflammation leads to a condition of relative energy metabolism deficiency that is exacerbated by cancer therapy-induced mitochondrial dysfunction. This will be done by determining the association between metabolic reprogramming and behavioral fatigue before assessing whether intensifying mitochondrial damage exacerbates the behavioral and metabolic phenotypes of fatigue while preventing mitochondrial damage has the reverse effect. In Aim 3, we will test the hypothesis that activation of cytosol DNA sensors by self DNA leaking from mitochondria and cell nuclei triggers this whole process. This research should help understand and treat cancer-related fatigue.

项目摘要 - 与癌症相关的疲劳是经历的最常见和破坏性症状之一由患者。它通常在诊断时存在，整个治疗过程中都会恶化，并且在此之后持续在很大一部分患者中停止治疗。负责疲劳的特定机制仍然是未知的。因此，没有用于疲劳和主要的机制引导疗法对报告严重疲劳的患者的方法是疲劳自我管理中的教育和咨询。尽管能源保护是管理疲劳的重要策略，但这种可能性的可能性与癌症相关的疲劳源于能量代谢的改变。现在项目填补了这个空白。我们的工作假设是，与癌症相关的疲劳是肿瘤对生物体施加的过量代谢需求和炎症可能相关和。线粒体导致这种情况导致的相对代谢效率恶化响应化学疗法和放射疗法会在外周组织和大脑中发展的损伤。到检验我们的假设，我们将使用两种癌症的癌模型顺铂和局部辐照，一种非炎症模型，模仿了人类乳头状瘤病毒相关的头部和颈部癌和由刘易斯肺癌代表的炎症模型。我们将衡量行为在这两种情况下，疲劳都通过改善自愿车轮运行和动机行为改变的疲劳解释疲劳的动机组成部分。在AIM 1中，我们将确定炎症是否相关随着肿瘤及其治疗，需要向大脑传播疲劳。这将由在介入之前，将外围和大脑中炎症的时间过程与疲劳的时间过程进行比较要么通过被动免疫阻断免疫信号分子，要么代替先天免疫细胞介导周围和大脑中的炎症过程。在AIM 2中，我们将检验以下假设。癌症和注射的代谢重编程导致相对能量代谢的条件癌症治疗引起的线粒体功能障碍加剧的缺乏。这将由在评估是否是否加强线粒体损伤加剧了疲劳的行为和代谢表型防止线粒体损伤具有相反的效果。在AIM 3中，我们将检验以下假设。通过从线粒体和细胞核泄漏的自DNA泄漏的细胞质DNA传感器触发了整个过程。这研究应有助于理解和治疗与癌症相关的疲劳。