Mechanism Underlying Sleep Disruption by Mammary Tumors

摘要 充足的睡眠数量和质量是保持最佳身心健康的关键。的确， 睡眠不足会影响许多重要的生理功能，损害认知能力和 情绪调节。被诊断为乳腺癌的患者睡眠障碍的风险特别高， 睡眠障碍可能会影响疾病的进展，因为更具侵袭性的肿瘤 在通常睡眠时间较少的女性中观察到。尽管有证据表明睡眠障碍正在出现 在癌症患者被诊断之前，以及潜在的破坏性后果，肿瘤的病因- 诱发性睡眠障碍仍不清楚。此R21应用程序的目标是确定生理 乳腺肿瘤损害睡眠的机制。拟议研究的指导性假设 是乳腺肿瘤增加了血清Ghrelin浓度，从而改变了增食欲素-下分泌素的活性 (哦)神经元，进而扰乱睡眠。这项提议代表着对生长激素释放素在癌症中的首次检查- 相关的睡眠障碍。我们的初步数据表明，乳腺肿瘤表达Ghrelin mRNA， 显著提高血清Ghrelin浓度，并改变睡眠。我们还展示了乳房 肿瘤增加了下丘脑中激活的增食欲素/下丘脑(OH)神经元的数量 对睡眠-觉醒调节至关重要的细胞。目标1将使用融合的药理学和遗传学(CRISPR) Ghrelin是下丘脑OH活性改变和睡眠改变的原因因素这一假设的检验方法 在荷瘤小鼠中的破坏。Aim 2将使用DREADD方法来确定OH神经元 在肿瘤扰乱睡眠的原因中，外侧下丘脑起着一定的作用。总而言之，拟议的研究将 广泛描述了乳腺肿瘤对睡眠的影响以及潜在的 Ghrelin浓度升高和OH神经元活动改变的干扰作用。的长远目标 这项研究旨在改善癌症患者的身心健康，以及他们的生活质量， 通过从癌症诊断开始的睡眠正常化；实现这一目标的第一步是 确定肿瘤改变睡眠的机制。

ABSTRACT Sufficient quantity and quality of sleep is critical for maintaining optimal physical and mental health. Indeed, inadequate sleep can influence many crucial physiological functions and impair cognitive performance and mood regulation. Patients diagnosed with breast cancer are at particularly high risk for sleep disorders, and disordered sleep may influence the progression of their disease as more aggressive tumors have been observed among women who routinely sleep fewer hours. Despite evidence of sleep disorders emerging prior to diagnosis in cancer patients, and the potentially devastating consequences, the etiology of tumor- induced sleep disorders remains unknown. The goal of this R21 application is to determine the physiological mechanisms through which mammary tumors impair sleep. The guiding hypothesis of the proposed research is that mammary tumors increase serum ghrelin concentration, which alters the activity of orexin-hypocretin (OH) neurons, and in turn disrupts sleep. This proposal represents the first examination of ghrelin in cancer- related sleep disruption. Our preliminary data demonstrate that mammary tumors express ghrelin mRNA, significantly elevate serum ghrelin concentrations, and alter sleep. We also have shown that mammary tumors increase the number of activated orexin/hypocretin (OH) neurons in the hypothalamus, a population of cells critical for sleep-wake regulation. Aim 1 will use converging pharmacological and genetic (CRISPR) approaches to test the hypothesis that ghrelin is a causal factor in altered hypothalamic OH activity and sleep disruption among tumor bearing mice. Aim 2 will use a DREADD approach to establish whether OH neurons in the lateral hypothalamus play a causal role in tumor-disrupted sleep. Together, the proposed studies will provide an extensive characterization of the effects of mammary tumors on sleep and the potentially disruptive role of increased ghrelin concentration and altered OH neuronal activity. The long-range goal of this research is to improve the mental and physical health of cancer patients, as well as their quality of life, through the normalization of sleep beginning at cancer diagnosis; the first step in achieving this goal is determining the mechanisms through which tumors alter sleep.