Mechanism Underlying Sleep Disruption by Mammary Tumors

乳腺肿瘤扰乱睡眠的机制

• 批准号: 10651086
• 负责人: Anne Courtney DeVries
• 金额: $ 21.32万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651086
• 关键词: Affect; Behavior; Brain; Breast; Breast Cancer Patient; Breast Cancer survivor; Cancer Etiology; Cancer Patient; Cancer Survivor; Cells; Data; Detection; Diagnosis; Disease; Disease Progression; Etiology; Goals; Health; Hormones; Hour; Hypothalamic structure; Impaired cognition; Impairment; Incidence; Individual; Lateral; Malignant Neoplasms; Mammary Neoplasms; Mental Health; Messenger RNA; Metabolism; Mus; Neurons; Outcome; Patients; Personal Satisfaction; Physiological; Physiology; Play; Population; Quality of life; Regulation; Research; Resolution; Role; Serum; Signal Transduction; Sleep; Sleep Architecture; Sleep Deprivation; Sleep Disorders; Sleep Fragmentations; Sleep disturbances; Specificity; Supportive care; Survivors; Symptoms; Testing; Woman; antagonist; biological systems; cancer diagnosis; cognitive performance; designer receptors exclusively activated by designer drugs; experience; experimental study; feeding; genetic approach; ghrelin; high risk; hypocretin; improved; improvement on sleep; individual variation; malignant breast neoplasm; mood regulation; neural circuit; neurotransmission; pharmacologic; physical conditioning; psychologic; sleep quality; social; tumor; tumor progression

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.

摘要 充足的睡眠量和质量对于保持最佳的身心健康至关重要。的确， 睡眠不足会影响许多重要的生理功能并损害认知能力， 情绪调节被诊断患有乳腺癌的患者患睡眠障碍的风险特别高， 睡眠障碍可能会影响他们的疾病的进展，因为更积极的肿瘤已经 在睡眠时间较少的女性中观察到。尽管有证据表明睡眠障碍 在癌症患者诊断之前，以及潜在的破坏性后果，肿瘤的病因学- 引起的睡眠障碍仍然未知。本R21应用程序的目标是确定生理 乳腺肿瘤损害睡眠的机制。拟议研究的指导假设 乳腺肿瘤增加了血清生长激素释放肽的浓度，这改变了食欲素-下丘脑泌素的活性， (OH)神经元，进而扰乱睡眠。这项提案代表了饥饿素在癌症中的首次研究- 与睡眠中断有关。我们的初步数据表明，乳腺肿瘤表达ghrelin mRNA， 显著升高血清胃饥饿素浓度并改变睡眠。我们还表明，乳腺癌 肿瘤增加了下丘脑中激活的食欲素/下丘脑泌素（OH）神经元的数量， 睡眠-觉醒调节的关键细胞。目标1将使用聚合药理学和遗传学（CRISPR） 方法来测试的假设，生长激素释放肽是改变下丘脑OH活性和睡眠的因果关系的因素 在荷瘤小鼠中的破坏。目标2将使用DREADD方法来确定OH神经元是否 在肿瘤干扰的睡眠中发挥因果作用。拟议的研究将共同 提供了乳腺肿瘤对睡眠影响的广泛表征， 增加的ghrelin浓度和改变的OH神经元活性的破坏性作用。长期目标是 这项研究是为了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。