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: 10800964
• 负责人: LEAH M PYTER
• 金额: $ 3.15万
• 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 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10800964
• 关键词: Adrenal Glands; Affect; Anti-Inflammatory Agents; Arrhythmia; Attenuated; Behavior; Behavioral; Brain; Breast Cancer survivor; Cancer Patient; Chronobiology; Circadian Dysregulation; Circadian Rhythms; Corticosterone; Corticotropin; Fatigue; Genes; Genetic; Glucocorticoids; Goals; Health; Hormones; Human; Inflammation; Intervention; Jet Lag Syndrome; Knowledge; Light; Lupus; Malignant Neoplasms; Melatonin; Mission; Mus; Neurosciences; Oncology; Parents; Pathway interactions; Patients; Periodicity; Peripheral; Pharmaceutical Preparations; Physiologic pulse; Physiology; Pituitary Gland; Planning Techniques; Plasma; Population; Public Health; Quality of life; Research; Role; Running; Stem cell transplant; Testing; United States National Institutes of Health; Work; cancer therapy; chemotherapy; circadian; circadian pacemaker; clinical practice; comorbidity; cytokine; design; falls; hypothalamic-pituitary-adrenal axis; improved; innovation; mortality; mouse model; neuroinflammation; novel; parent grant; pharmacologic; response; 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 peripheral (adrenal) clock function contributing to fatigue. The rationale for this work is that circadian cir- cuitry disruption is an understudied, relevant pathway in psycho-oncology research that could elucidate mecha- nisms and new, rhythm-focused interventions. One specific aim is proposed to test the central hypothesis us- ing our novel breast cancer “survivor” mouse model: What is the relationship between peripheral (supplement) and master (parent) circadian clocks after chemotherapy? Three hypotheses will be tested to answer this questions. H1: Attenuated glucocorticoid responses to light challenges are correlated with longer SCN re-en- trainment duration in chemotherapy-treated mice. Corticosterone and melatonin will be quantified during the light-pulse and jet lag challenges in the parent grant. The rhythmicity of these hormones and their relationships to wheel running re-entrainment will be assessed. H2: Chemotherapy disruption of clock genes rhythms and circulating GCs are independent of the HPA axis. Plasma ACTH and corticosterone and clock genes in the PVN, adrenals, and pituitary will be assessed every 2 h over 24 h. H3: Neuroinflammation drives chemother- apy-induced GC arrhythmia. Corticosterone rhythms will be analyzed during anti-inflammatory SCN treatment and cytokines will be quantified in plasma. 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 trans- lational model and the circadian genetic and pharmacological techniques planned. This research will result in essential new knowledge about how common cancer treatments affect auxiliary clocks, which modulates physi- ology and behavior (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 pharmacologi- cal 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-- 证明癌症患者的衰弱行为后遗症，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， 其外周（肾上腺）时钟功能导致疲劳。这项工作的基本原理是昼夜循环- 在心理肿瘤学研究中，文化破坏是一个未充分研究的相关途径，可以阐明机制， 和新的、以节奏为中心的干预措施。一个具体的目标是提出来测试我们的中心假设- 使用我们的新型乳腺癌“幸存者”小鼠模型：外周（补充） 和主（父母）生物钟化疗后？三个假设将被测试来回答这个问题 问题. H1：减弱的糖皮质激素对光刺激的反应与更长的SCN再激活相关。 化疗处理的小鼠中的训练持续时间。皮质酮和褪黑激素将在 光脉冲和时差挑战在父母补助金。这些激素的节律性和它们之间的关系 将评估车轮运行的再夹带。H2：化疗对生物钟基因节律的破坏， 循环GC与HPA轴无关。血浆促肾上腺皮质激素和皮质酮和时钟基因在 PVN、肾上腺和垂体将在24小时内每2小时评估一次。H3：神经炎症驱动化疗- apy诱导的GC心律失常。将在抗炎SCN治疗期间分析皮质酮节律 并且将定量血浆中的细胞因子。这项研究在概念上是创新的，因为使用 昼夜节律方法是心理肿瘤学的新方法。它在技术上也是创新的，通过上级反式- 国家模型和昼夜节律的遗传和药理学技术计划。这项研究将导致 关于常见癌症治疗如何影响辅助时钟的基本新知识，这些辅助时钟调节生理 学和行为（即，超越疲劳）。结果将提供急需的证据，使基于昼夜节律的 在临床实践中的方法标准，以及通知新的昼夜节律导向药理学的设计， CAL和非药物干预。这项研究适用于其他癌症和非肿瘤 接受化疗的人群（例如，干细胞移植、狼疮）。