Chemotherapy-induced circadian master clock disruptions and fatigue

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）。

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).