Chemotherapy-induced circadian master clock disruptions and fatigue

项目摘要/摘要 了解与以下相关的昼夜节律紊乱的原因和机制 癌症治疗过程中的疲劳仍不清楚。这种目前的缺陷意味着成功的癌症治疗- MENT达不到其潜力，患者的先前生活质量仍然难以捉摸。我们的长期目标是- 证实癌症患者的衰弱行为后遗症，从而改善生活质量，其他共病， 和死亡率。因此，这里的总体目标是确定昼夜节律中断的潜在作用是一种乐趣-- 化疗促进癌症相关性疲劳的基本途径。的确，强劲的昼夜节律- 几乎所有生理的节律都是非常保守的；这些节律的去同步化导致负值。 健康和行为后果。中心假设是化疗引起的炎症抑制- 它的外周(肾上腺)时钟功能导致疲劳。这项工作的基本原理是昼夜节律- 在心理肿瘤学研究中，丘脑干扰是一种未被充分研究的相关途径，可以阐明其机制-- 新的、以节奏为重点的干预措施。提出了一个具体的目标来检验我们的中心假设-- 我们新的乳腺癌幸存者小鼠模型：外周有什么关系(补充) 化疗后掌握(父母)生物钟？我们将测试三个假设来回答这个问题。 问题。H1：糖皮质激素对轻度挑战的反应减弱与SCN再发病时间更长相关 化疗小鼠的训练时间。皮质酮和褪黑素将在 父奖助金中的光脉冲和时差挑战。这些激素的节律性及其相互关系 将对车轮运行时的再卷吸进行评估。H2：化疗扰乱时钟基因节律和 循环GC独立于HPA轴。血浆促肾上腺皮质激素、皮质酮和时钟基因 脑室旁核、肾上腺和垂体将在24小时内每隔2小时进行一次评估。H3：神经炎症驱动化疗- APY诱发的GC心律失常。在抗炎SCN治疗过程中将分析皮质酮的节律 而细胞因子将在血浆中进行量化。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肿瘤学来说是一种新方法。它也是技术创新的方式，通过优越的跨- 国家模型和计划中的昼夜遗传和药理学技术。这项研究将导致 关于常见癌症治疗如何影响辅助钟的基本新知识，辅助钟调节生理- 心理和行为(即超越疲劳)。结果将提供亟需的证据，以使昼夜节律 临床实践中的方法标准，以及指导设计新的昼夜节律导向的药理作用。 CAL和非药物干预。这项研究也适用于其他癌症和非肿瘤领域。 接受化疗(如干细胞移植、狼疮)的人群。

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).