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.

抽象的 足够的睡眠数量和质量对于维持最佳的身心健康至关重要。的确， 睡眠不足会影响许多关键的生理功能，并损害认知表现和 情绪调节。被诊断出患有乳腺癌的患者患睡眠障碍的风险特别高， 由于更具侵略性的肿瘤已经是 在常规睡觉的女性中观察到。尽管出现了睡眠障碍的证据 在癌症患者诊断之前，以及潜在的毁灭性后果，肿瘤的病因 诱发的睡眠障碍仍然未知。该R21应用的目的是确定生理 乳腺肿瘤损害睡眠的机制。拟议研究的指导假设 是乳腺肿瘤会增加血清血清素浓度，从而改变奥脱甲蛋白 - 甲状腺素的活性 （OH）神经元，进而破坏睡眠。该提议代表了癌症中生长素释放蛋白的首次检查 - 相关的睡眠中断。我们的初步数据表明，乳腺肿瘤表达发芽素mRNA， 显着升高血清生长素蛋白浓度，并改变睡眠。我们还表明了乳房 肿瘤增加了下丘脑中活化的Orexin/dybocretin（OH）神经元的数量，一个种群 细胞对睡眠效果调节至关重要。 AIM 1将使用融合的药理学和遗传（CRISPR） 测试生长素蛋白是下丘脑OH活性改变和睡眠的因素的假设的方法 肿瘤小鼠的破坏。 AIM 2将使用Dreadd方法来确定是否oh神经元 在侧丘脑中，下丘脑在肿瘤干扰的睡眠中起因果作用。拟议的研究一起将 提供乳腺肿瘤对睡眠和潜在的影响的广泛表征 升高的生长素素浓度和OH神经元活性改变的破坏性作用。远程目标 这项研究是为了改善癌症患者的心理和身体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。