Circadian clock suppression in cancer-related fatigue

描述（由申请人提供）：昼夜节律或每日节律调节生理反应。稳健的每日节律预测癌症患者的预后改善，独立于性能状态测量。昼夜节律的破坏与睡眠质量差和消极情绪、疲劳和生活质量下降有关。当病人在夜间不再睡觉时，在家中照顾病人的能力往往会丧失。肿瘤抑制昼夜节律和损害生活质量的机制尚不清楚。我们假设肿瘤诱导的细胞因子释放可能直接作用于神经系统，驱动昼夜节律，这种作用可能导致疲劳和昼夜节律破坏。先前的研究表明，细胞因子TGF-1和神经调节蛋白-1的中枢给药和IFN-1的全身给药可以破坏仓鼠和小鼠的行为节律。作为肿瘤诱导的破坏的动物模型，我们将确定外周施用TGF-1和neuregulin-1是否可以类似地破坏小鼠的运动活动节律。我们将确定细胞因子是否可以抑制分离的视交叉上核（SCN）、免疫系统器官、胸腺和脾脏以及其他组织（肺和乳腺）表达的节律。进一步的实验将评估用于化疗的表皮生长因子受体（EGFR）酪氨酸激酶激活的阻断剂厄洛替尼或吉非替尼是否可以改善TGF-1破坏后的昼夜节律规律性和幅度。这些实验旨在模拟显示患者中此类效应的临床数据。我们将用动物确定厄洛替尼或吉非替尼给药的最佳时间，以最大限度地提高对昼夜节律系统的潜在益处。这项研究将增加我们对肿瘤生长影响昼夜节律系统的生物学机制的理解。我们将描述生物钟输出抑制对免疫系统功能和选择器官内源性节律的影响。我们的研究将阐明这种作用是否可由细胞因子介导，作用是外周还是中枢，以及给予特异性细胞因子受体阻滞剂后生活质量改善的临床报告是否可归因于昼夜节律的改善。这项研究将直接应用于EGFR阻滞剂的临床使用，通过调查这些化合物的最佳时机的基本原理。癌症患者经常遭受昼夜节律紊乱，导致睡眠质量差、消极情绪、疲劳和生活质量降低。肿瘤诱导细胞因子释放，这可能是昼夜节律中断和随后的疲劳的原因。通过用特定化合物阻断细胞因子的作用，我们希望阐明细胞因子对免疫和昼夜节律系统的下游作用。细胞因子阻滞剂给药后生活质量改善的临床报告可能归因于昼夜节律的改善。

DESCRIPTION (provided by applicant): Circadian or daily rhythms modulate physiological responses. Robust daily rhythms are predictive of improved prognosis for cancer patients, independent of performance status measures. Disruption of circadian rhythms is associated with poor sleep quality and negative mood, fatigue, and reduced quality of life. The ability to care for a patient at home is often lost when the patient no longer sleeps during the night. The mechanism by which tumors suppress circadian rhythms and impair quality of life is unknown. We hypothesize that cytokine release induced by tumors may act directly in the neural system driving circadian rhythms and this action may induce fatigue and circadian rhythm disruption. Previous studies have shown that central administration of the cytokines TGF-1 and neuregulin-1 and systemic administration of IFN-1 can disrupt behavioral rhythms in hamsters and mice. As an animal model of tumor-induced disruption, we will determine if peripheral administration of TGF-1 and neuregulin-1 can similarly disrupt locomotor activity rhythms in mice. We will determine if cytokines can suppress the rhythms expressed by isolated suprachiasmatic nucleus (SCN), immune system organs, thymus and spleen, and other tissues (lung and mammary gland). Further experiments will assess if erlotinib or gefitinib, blockers of epidermal growth factor receptor (EGFR) tyrosine kinase activation used for chemotherapy, can improve circadian rhythm regularity and amplitude following disruption by TGF-1. These experiments are designed to mimic clinical data showing such effects in patients. We will determine with animals the optimal timing for administration of erlotinib or gefitinib to maximize the potential benefit to the circadian system. This research will increase our understanding of the biological mechanism by which tumor growth can impact the circadian system. We will describe effects of circadian clock output suppression on immune system function and on rhythms endogenous to select organs. Our studies will clarify if such effects could be mediated by cytokines, if action is peripheral or central, and if clinical reports of improved quality of life following administration of specific cytokine receptor blockers might be attributable to improved circadian regularity. This research will apply directly to clinical use of EGFR blockers, by investigating a rationale for optimal timing of these compounds. Cancer patients often suffer from disrupted circadian rhythms resulting in poor sleep quality, negative mood, fatigue and reduced quality of life. Tumors induce cytokine release, which may be responsible for circadian disruption and subsequent fatigue. By blocking the action of cytokines with specific compounds, we hope to clarify the downstream effects of cytokines on the immune and circadian systems. Clinical reports of improved quality of life after administration of cytokine blockers might be attributable to improved circadian rhythms.