Chemotherapy-induced circadian master clock disruptions and fatigue

化疗引起的昼夜节律主时钟中断和疲劳

• 批准号: 10585143
• 负责人: LEAH M PYTER
• 金额: $ 54.82万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-23 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585143
• 关键词: Address; Adjuvant Chemotherapy; Affect; Alcohols; Anti-Inflammatory Agents; Basic Science; Behavior; Behavior assessment; Behavioral; Biological; Biological Clocks; Biometry; Brain; Breast Cancer Patient; Breast Cancer survivor; Cancer Patient; Cells; Chemotherapy-Oncologic Procedure; Chronobiology; Circadian Dysregulation; Circadian Rhythms; Clinical Data; Cognitive; Cues; Data; Diabetes Mellitus; Etiology; Eukaryota; Fatigue; Foundations; Genes; Genetic; Goals; Health; Health Benefit; Hospital Costs; Human; Hypothalamic structure; Inflammation; Intervention; Jet Lag Syndrome; Knowledge; Light; Lupus; Malignant Neoplasms; Mammary Neoplasms; Medical Oncology; Mental Health; Methods; Mission; Molecular; Motivation; Neurosciences; Oncology; Operative Surgical Procedures; Outcome; Pacemakers; Paclitaxel; Pathway interactions; Patients; Periodicity; Pharmaceutical Preparations; Phase; Phase response curves; Phototherapy; Physical assessment; Physiological; Physiology; Planning Techniques; Population; Predisposition; Psychoneuroimmunology; Public Health; Quality of life; Research; Research Project Grants; Resolution; Rest; Role; Running; Scientist; Signal Transduction; Stem cell transplant; Survival Rate; Survivors; Symptoms; System; Systems Biology; Testing; United States National Institutes of Health; Work; behavior change; cancer therapy; chemotherapy; circadian; circadian biology; circadian pacemaker; clinical practice; comorbidity; design; disorder risk; experimental study; falls; glial activation; hazard; improved; in vivo; innovation; loved ones; malignant breast neoplasm; mortality; mouse model; neuroinflammation; novel; pharmacologic; prevent; shift work; suprachiasmatic nucleus; translational model; virtual

PROJECT SUMMARY/ABSTRACT Understanding the causes and mechanisms underlying circadian rhythm disruptions that are associated with fatigue during cancer treatment remains unclear. This current deficiency means that successful cancer treat- ment falls short of its potential and prior quality-of-life remains elusive for patients. Our long-term goal is to im- prove debilitating behavioral sequelae in cancer patients, thus improving quality-of-life, other comorbidities, and mortality. Thus, the overall objective here is to establish the potential role of circadian disruption as a fun- damental pathway by which chemotherapy promotes cancer-associated fatigue. Indeed, robust circadian rhyth- micity of virtually all physiology is extremely well-conserved; desynchrony of these rhythms leads to negative health and behavioral consequences. The central hypothesis is that chemotherapy-induced inflammation inhib- its SCN function leading to fatigue. The rationale for this work is that circadian circuitry disruption is an under- studied, relevant pathway in psycho-oncology research that could elucidate mechanisms and new, rhythm-fo- cused interventions. Three specific aims are proposed to test the central hypothesis using our novel breast cancer “survivor” mouse model. Aim 1 will determine the ability of the master clock to entrain after chemother- apy. Behavioral SCN rhythm adaptations to environmental challenges will be assessed. Aim 2 will identify the role of central inflammation in master clock disruptions after chemotherapy. The role of chemotherapy-induced neuroinflammation on SCN molecular and behavioral rhythms will be quantified. The potential resolution of fa- tigue will also be assessed. Aim 3 will determine the role of circadian disruption in chemotherapy-induced fa- tigue. Genetic and pharmacological SCN timing manipulations will precede a battery of behavioral assess- ments of the physical, motivation, and cognitive components of fatigue. In vivo and ex vivo circadian timing ap- proaches combined with systems-, cellular-, and molecular-level analyses will pinpoint the effects of two regi- mens of chemotherapy on master oscillator circadian circuitry relevant to cancer-related behavioral comorbidi- ties. The proposed research is conceptually innovative because using circadian approaches is new to psycho- oncology. It is also technically innovative by way of the superior translational model and the circadian genetic and pharmacological techniques planned. This research will result in essential new knowledge about how com- mon cancer treatments affect the pacemaker, which is crucial to extensive downstream physiology and behav- ior (i.e., beyond fatigue). Results will provide much needed evidence to make circadian-based approaches standard in clinical practice, as well as inform the design of novel circadian-directed pharmacological and non- pharmacological interventions. This research is applicable to other cancers and in non-oncological populations treated with chemotherapy (e.g., stem cell transplant, lupus).

项目总结/摘要 了解与糖尿病相关的昼夜节律紊乱的原因和机制 癌症治疗期间的疲劳仍然不清楚。目前的缺陷意味着成功的癌症治疗- 但福尔斯达不到其潜力，并且患者的先前生活质量仍然难以捉摸。我们的长远目标是-- 证明癌症患者有使人衰弱的行为后遗症，从而改善生活质量、其他合并症， and mortality.因此，这里的总体目标是建立昼夜节律中断作为一种乐趣的潜在作用- 化疗促进癌症相关疲劳的重要途径。实际上，强大的昼夜节律- 几乎所有的生理活动都是非常保守的;这些节律的破坏导致负性的 健康和行为后果。中心假设是化疗诱导的炎症反应可能是一种慢性炎症反应， 其SCN功能导致疲劳。这项工作的基本原理是，昼夜节律电路中断是一个下- 研究，心理肿瘤学研究的相关途径，可以阐明机制和新的，节奏， 干预措施。提出了三个具体的目标，以测试中心的假设，使用我们的新乳房 癌症“幸存者”小鼠模型。目标1将确定主时钟在化学物质之后携带的能力- - 是的将评估行为SCN节律对环境挑战的适应。目标2将确定 化疗后中枢炎症在主时钟中断中的作用化疗诱导的作用 将量化神经炎症对SCN分子和行为节律的影响。FA的潜在分辨率- 还将对tigue进行评估。目的3将确定昼夜节律紊乱在化疗诱导的fa- 老虎。遗传和药理学SCN定时操作将在一系列行为评估之前进行- 疲劳的身体、动机和认知成分的部分。体内和离体昼夜节律计时 结合系统、细胞和分子水平分析的方法将查明两个区域的影响， 化疗对与癌症相关行为共病相关的主振荡器昼夜节律回路的影响 关系的拟议的研究在概念上是创新的，因为使用昼夜节律方法对心理学来说是新的， 肿瘤学通过上级翻译模型和昼夜节律遗传学， 和药理学技术。这项研究将导致关于如何COM的基本新知识- 癌症治疗会影响起搏器，这对广泛的下游生理学和心脏病至关重要。 IOR（即，超越疲劳）。结果将提供急需的证据，使基于昼夜节律的方法 标准的临床实践，以及通知设计新的昼夜节律导向的药理学和非 药物干预。这项研究适用于其他癌症和非肿瘤人群 用化疗治疗（例如，干细胞移植、狼疮）。