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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：
10661646
负责人：
Robert Dantzer
金额：
$ 39.98万
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/10661646
关键词：
Affect Aftercare Attenuated Behavior Behavioral Biological Brain CASP1 gene CSF1 gene Cancer Model Cancer Patient Cell Nucleus Cells Central Nervous System Chemotherapy and/or radiation 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 Neurosecretory Systems Organ Organism Oxidative Phosphorylation Passive Immunization Pathway interactions Patients Peripheral Physical activity Process Proliferating Radiation therapy Reporting Repression Research Research Project Grants Running Self Management Severities Signaling Molecule Skeletal Muscle Stimulator of Interferon Genes Symptoms Syndrome Taxes Testing Time Tissues Warburg Effect Withholding Treatment Work aerobic glycolysis antagonist behavior measurement behavioral phenotyping cancer cachexia cancer cell cancer therapy 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

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-癌症相关疲劳是最常见和最具破坏性的症状之一

项目成果

期刊论文数量（42）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Resilience and immunity.

DOI：
10.1016/j.bbi.2018.08.010
发表时间：
2018-11
期刊：
Brain, behavior, and immunity
影响因子：
0
作者：
Dantzer R;Cohen S;Russo SJ;Dinan TG
通讯作者：
Dinan TG

Inhibition of Tryptophan Catabolism Is Associated With Neuroprotection During Zika Virus Infection.

DOI：
10.3389/fimmu.2021.702048
发表时间：
2021
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Marim FM;Teixeira DC;Queiroz-Junior CM;Valiate BVS;Alves-Filho JC;Cunha TM;Dantzer R;Teixeira MM;Teixeira AL;Costa VV
通讯作者：
Costa VV

Lipopolysaccharide does not alter behavioral response to successive negative contrast in mice.