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).

项目摘要/摘要 了解与之相关的昼夜节律中断的原因和机制 癌症治疗期间的疲劳尚不清楚。当前的缺乏意味着成功的癌症治疗 - 对于患者而言，其潜在的潜力和先前的生活质量仍然难以捉摸。我们的长期目标是 证明癌症患者的行为后遗症使人衰弱，从而改善了生活质量，其他合并症， 和死亡率。这是，这里的总体目的是确定昼夜节律的潜在作用作为一种有趣的 化学疗法促进癌症相关疲劳的典型途径。确实，强大的昼夜节律 - 几乎所有生理学的粉红色都非常保存；这些节奏的偏斜导致负面 健康和行为后果。中心假设是化学疗法诱导的感染抑制 它的外围（肾上腺）时钟功能导致疲劳。这项工作的理由是昼夜节律 戒烟破坏是心理肿瘤研究中的一种相关途径，可以阐明机甲 NISM和新的，以节奏为重点的干预措施。提出了一个具体目标来检验中心假设。 为我们的新型乳腺癌“幸存者”小鼠模型：外围（补充）之间的关系是什么 化学疗法后的（父母）昼夜节律？将测试三个假设以回答这个问题 问题。 H1：糖皮质激素对光挑战的反应与较长的SCN重新相关 化学疗法治疗的小鼠的培训持续时间。皮质酮和褪黑激素将在期间进行量化 父母赠款中的轻脉冲和喷气滞后挑战。这些骑兵及其关系的节奏性 将评估转轮运行重新入口。 H2：时钟基因节奏的化学疗法破坏和 循环GC与HPA轴无关。血浆ACTH和皮质酮和时钟基因 在24小时内，每2小时一次评估PVN，肾上腺和居民。 H3：神经炎症驱动化学驱动 - APY诱导的GC心律不齐。在抗炎SCN治疗期间，将分析皮质酮节奏 细胞因子将在血浆中进行定量。拟议的研究在概念上是创新的，因为使用 昼夜节律是心理肿瘤学的新方法。它在技术上也是通过上级跨性别的方式创新的 层压模型以及计划的昼夜节律遗传和药物技术计划。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，这调节了物理 神学和行为（即，超越疲劳）。结果将提供急需的证据，以使昼夜节律 在临床实践方面取得了标准，并为新颖的昼夜节律药物的设计提供了信息。 CAL和非药理干预措施。这项研究适用于其他癌症和非肿瘤学 接受化学疗法治疗的种群（例如干细胞移植，狼疮）。