Unraveling the Associations of Molecular-Genetic Bioenergetics and Chemotherapy-Induced Fatigue Symptoms in Patients with Breast Cancer
揭示乳腺癌患者分子遗传学生物能学与化疗引起的疲劳症状之间的关联
基本信息
- 批准号:10684326
- 负责人:
- 金额:$ 20.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-15 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AccelerationAdenosine TriphosphateAdverse effectsAffectiveAnthracyclineAntibioticsBehaviorBehavioralBiochemicalBioenergeticsBiological MarkersBlood PlateletsBreast Cancer PatientBreast Cancer TreatmentBreast Cancer therapyCancer EtiologyCancer PatientCardiotoxicityCell Cycle ProgressionCellsChemotherapy-Oncologic ProcedureChronic Fatigue SyndromeCognitiveComplexCouplingDefectDevelopmentDimensionsDiseaseDistressDoseDoxorubicinElderlyElectron TransportEnergy MetabolismEquilibriumEsophageal AdenocarcinomaExhibitsFatigueFoundationsGene ExpressionGenerationsGenesGeneticHealthHeterogeneityImpaired cognitionImpairmentIndividualInjuryInterruptionInterventionInvestigationLifeLinkMalignant NeoplasmsMalignant neoplasm of prostateMeasuresMental DepressionMitochondriaMitoticMolecular GeneticsMotivationMusMuscleMyocardiumNeuropathyNormal tissue morphologyNutraceuticalOutcomeOxidation-ReductionOxidative PhosphorylationOxidative StressPathway interactionsPatientsPeripheral Blood Mononuclear CellPharmaceutical PreparationsProteinsQuality of lifeRadiation therapyReactive Oxygen SpeciesRegimenReportingResearch Project GrantsRespiratory ChainSensorySeveritiesSleep disturbancesSymptomsTherapeutic AgentsTimeTissuesToxic effectcancer biomarkerscarcinogenesischemotherapeutic agentchemotherapycognitive functiondesigndiagnostic biomarkerexhaustionexperiencehealth related quality of lifeheart functionimprovedinsightmalignant breast neoplasmmitochondrial dysfunctionmuscle strengthnovelpersonalized managementpharmacologicpreclinical studyreduced muscle strengthside effectsymptom managementsymptom sciencetargeted treatmenttherapeutic targettherapeutically effectivetumor
项目摘要
PROJECT SUMMARY/ABSTRACT
Cancer-related fatigue (CRF) occurs in 82%-96% of cancer patients receiving chemotherapy (CT) and it is
one of the most prevalent side effects of CT in patients with breast cancer. CT-induced CRF is a distressing,
persistent sense of exhaustion related to the disease or its treatment, and negatively impacts health outcomes
(e.g., depression, sleep disturbance, poor quality of life). Despite various attempts to investigate the etiology of
CRF, the biochemical mechanisms remain elusive. The proposed study aims to investigate the molecular-
genetic pathway of mitochondrial bioenergetics and their association with CT-induced CRF symptoms
experienced by patients with breast cancer receiving CT-containing anthracyclines, compared to those with
non-anthracycline-based CT. Anthracycline-based CT has been associated with mitochondrial dysfunction
through increased mitochondrial reactive oxygen species (ROS) and an induced decrease in muscle strength.
Deficiency of adenosine triphosphate (ATP) has been proposed as the basis of fatigue. Peripheral blood
mononuclear cells (PBMCs) of fatigued patients with prostate cancer has exhibited reduced ATP coupling
efficiency compared to those without fatigue. In patients with prostate cancer undergoing radiotherapy, we
found that CRF severity was significantly correlated with altered mitochondrial genes and impaired
mitochondrial oxidative phosphorylation (OXPHOS). In patients with breast cancer suffering from CT-induced
CRF, we intend to determine whether there is a similar altered expression of mitochondrial-related genes with
defective bioenergetics in PBMCs and platelets. We propose that the chemotherapeutic agent (anthracycline-
based regimen) targets cell cycle progression, which triggers genetic and cellular instability, altering expression
of mitochondrial genes and proteins, inducing reduced electron transport chain (ETC) enzymatic activity and
impaired OXPHOS, resulting in ATP depletion and excessive ROS generation, leading to the development and
intensification of CRF. This R21 proposal will reveal the linkage between changes in the molecular-
genetic pathway of mitochondrial bioenergetics and CT-induced CRF when controlling for relevant
covariates. Specific aims are to: (1) Characterize the profile of mitochondria-related genes associated with
CRF symptoms in patients with breast cancer receiving anthracycline-based CT, compared to patients with
non-anthracycline-based CT at baseline, midpoint, and endpoint of CT. (2) Identify the profile of mitochondrial
bioenergetics associated with CRF symptoms in patients with breast cancer receiving anthracycline-based CT,
compared to patients with non-anthracycline-based CT, at each time point. Understanding the molecular-
genetic bioenergetics underpinning CRF will provide novel insights needed for targeted approaches to mitigate
CT-induced CRF. The results will also advance symptom science, enable us to discover biomarkers, identify
therapeutic agents, support the design of nonpharmacological interventions, and initiate precision symptom
management to improve CRF.
项目摘要/摘要
癌症相关性疲劳(CRF)发生在82%-96%接受化疗(CT)的癌症患者中,
这是乳腺癌患者CT最常见的副作用之一。CT引起的CRF是一种令人痛苦的,
与疾病或其治疗相关的持续疲惫感,并对健康结果产生负面影响
(e.g.,抑郁、睡眠障碍、生活质量差)。尽管有各种各样的尝试来研究
CRF的生化机制仍然难以捉摸。这项研究旨在研究分子-
线粒体生物能量学的遗传途径及其与CT诱导的CRF症状的相关性
与接受含CT蒽环类药物治疗的乳腺癌患者相比,
非蒽环类CT。基于蒽环类的CT与线粒体功能障碍有关
通过增加线粒体活性氧(ROS)和诱导的肌肉力量下降。
三磷酸腺苷(ATP)缺乏被认为是疲劳的基础。外周血
疲劳的前列腺癌患者的单个核细胞(PBMC)表现出ATP偶联减少
与没有疲劳的人相比。在接受放疗的前列腺癌患者中,我们
发现CRF的严重程度与线粒体基因的改变显著相关,
线粒体氧化磷酸化(OXPHOS)。在患有CT诱导的乳腺癌患者中,
CRF,我们打算确定是否有一个类似的改变表达的肾脏相关基因,
PBMCs和血小板中的生物能量学缺陷。我们建议化疗药物(蒽环类-
基于方案)靶向细胞周期进程,其触发遗传和细胞不稳定性,改变表达
线粒体基因和蛋白质,诱导降低电子传递链(ETC)酶活性,
受损的OXPHOS,导致ATP耗竭和过量的ROS产生,导致发展和
强化CRF。这个R21的建议将揭示分子变化之间的联系-
线粒体生物能量学和CT诱导的CRF的遗传途径,当控制相关
协变量具体的目标是:(1)表征与Escherichia相关的基因谱,
接受蒽环类药物CT的乳腺癌患者的CRF症状,与接受
在基线、中点和CT终点时接受非蒽环类抗生素CT。(2)识别线粒体的轮廓
接受蒽环类药物CT的乳腺癌患者中与CRF症状相关的生物能量学,
在每个时间点,与非蒽环类药物为基础的CT患者相比。了解分子-
支持CRF的遗传生物能量学将为有针对性的方法提供新的见解,
CT诱发的CRF。这些结果也将推进症状科学,使我们能够发现生物标志物,
治疗药物,支持非药物干预措施的设计,并引发精确的症状
管理,以改善CRF。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Chao-Pin Hsiao其他文献
Chao-Pin Hsiao的其他文献
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{{ truncateString('Chao-Pin Hsiao', 18)}}的其他基金
Unraveling the Associations of Molecular-Genetic Bioenergetics and Chemotherapy-Induced Fatigue Symptoms in Patients with Breast Cancer
揭示乳腺癌患者分子遗传学生物能学与化疗引起的疲劳症状之间的关联
- 批准号:
10525505 - 财政年份:2022
- 资助金额:
$ 20.13万 - 项目类别:
Mitochondrial Bioenergetic Mechanism of Cancer Related Fatigue
癌症相关疲劳的线粒体生物能机制
- 批准号:
9274848 - 财政年份:2015
- 资助金额:
$ 20.13万 - 项目类别:
Mitochondrial Bioenergetic Mechanism of Cancer Related Fatigue
癌症相关疲劳的线粒体生物能机制
- 批准号:
9123678 - 财政年份:2015
- 资助金额:
$ 20.13万 - 项目类别:
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