Lithium, circadian rhythm, and bipolar disorder

锂、昼夜节律和双相情感障碍

• 批准号: 8098039
• 负责人: CHIAKI FUKUHARA
• 金额: $ 24.27万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8098039
• 关键词: Adverse effects; Affect; Biological Assay; Biology; Bioluminescence; Bipolar Disorder; Blood Cells; Cells; Cessation of life; Circadian Rhythms; Clinical; Darkness; Data; Dermatology; Development; Diagnostic; Disease; Effectiveness; Electronic Mail; Fibroblasts; Future; Generations; Genes; Genetic Screening; Genome; Goals; Human; In Vitro; Lithium; Luciferases; Manic; Medical; Mental Depression; Mental disorders; Methods; Modeling; Monitor; Mood stabilizers; Moods; Outcomes Research; Output; Pathogenesis; Patients; Peripheral; Personal Satisfaction; Pharmaceutical Preparations; Pharmacology; Physiological; Population; Predisposition; Proteins; Published Comment; Recurrence; Regulation; Reporter; Reporting; Research; Resistance; Schedule; Screening procedure; Serum; Sleep; Suicide; System; Testing; Therapeutic; Therapeutic Effect; Time; Universities; Variant; Well in self; circadian pacemaker; disability; high throughput screening; medical schools; patient population; prevent; professor; programs; promoter; response; years of life lost

For over fifty years, the mood stabilizer lithium has proven its efficacy in preventing recurrence of mania and suicide in bipolar patients more than any other drug. However, only a sub-population of patients benefit from lithium treatment, full benefits may not be apparent for several months, and lithium has adverse, sometimes toxic, side effects. Therefore, a simple, rapid and reliable assay to predict which patients will show a therapeutic response to lithium, which can be applied prior to treatment, is needed. In this proposal, the effects of lithium on mood stabilization and circadian rhythm expression in peripheral cells (fibroblasts) will be correlated in lithium-responsive and lithium-insensitive bipolar disorder patients, to determine whether circadian rhythm expression in human peripheral cells can be used to predict clinical lithium sensitivity in bipolar disorder patients. There is compelling evidence for a circadian component in the pathogenesis of at least some forms of bipolar disorder, e.g., lithium affects circadian rhythm expression, and scheduled sleepwake cycles and prolonged darkness stabilize mood swings. In addition, the feasibility of using peripheral cells to determine circadian rhythm expression in humans has been reported in a recent study. Having found that several physiological factors in blood cells are affected in bipolar disorder patients, it is probable that peripheral cells and circadian output can be used for a diagnostic assay for lithium responsiveness. A goal of our present proposal is to establish an assay system by which circadian rhythms can be monitored using human fibroblasts with a circadian reporter and real time bioluminescence monitoring, and to test the hypothesis that clinical response to lithium can be predicted using human peripheral cells. Therefore, specific aims will be: (1) To establish and optimize a screening method by which circadian rhythms can be monitored in human peripheral cells, and (2) to test the hypothesis that lithium differentially affects circadian Bmallbioluminescence rhythms in fibroblasts of lithium-responsive and lithium-insensitive patients. By testing the effects of lithium on circadian rhythm expression in human peripheral cells, we expect to establish an assay to pre-screen patients for lithium responsiveness prior to drug treatment, and, in future studies, to dissect the mechanisms responsible for bipolar disorder, particularly from the viewpoint of lithium sensitivity and circadian rhythm generation. The model and assay system should also be useful in medium to high throughput screening for new drugs to treat both lithium-responsive and -resistant patients with bipolar disorder.

五十多年来，情绪稳定剂锂已证明其在预防躁狂症和抑郁症复发方面的功效。 双相情感障碍患者的自杀率高于任何其他药物。然而，只有一小部分患者受益 锂盐治疗，全部益处可能要几个月才能显现出来，而且锂盐有时会产生不利影响 有毒、副作用。因此，需要一种简单、快速且可靠的检测方法来预测哪些患者会表现出 需要对锂产生治疗反应，可以在治疗前使用锂。在该提案中， 锂对外周细胞（成纤维细胞）的情绪稳定和昼夜节律表达的影响将 在锂敏感型和锂不敏感型双相情感障碍患者中进行相关性分析，以确定是否 人类外周细胞的昼夜节律表达可用于预测临床锂敏感性 双相情感障碍患者。有令人信服的证据表明昼夜节律因素参与了 at 的发病机制。 至少某些形式的双相情感障碍，例如，锂会影响昼夜节律的表达和预定的睡眠觉醒 周期和长时间的黑暗可以稳定情绪波动。另外，使用外围设备的可行性 最近的一项研究报告了利用细胞来确定人类昼夜节律表达的方法。发现后 双相情感障碍患者血细胞中的几种生理因素受到影响，很可能 外周细胞和昼夜节律输出可用于锂反应性的诊断测定。 我们目前提案的目标是建立一个可以监测昼夜节律的检测系统 使用具有昼夜节律报告器和实时生物发光监测的人类成纤维细胞，并测试 假设可以使用人类外周细胞来预测对锂的临床反应。因此，具体 目标是： (1) 建立和优化可监测昼夜节律的筛查方法 在人类外周细胞中，以及（2）检验锂对昼夜节律生物发光有不同影响的假设 锂反应性和锂不敏感患者的成纤维细胞节律。 通过测试锂对人体外周细胞昼夜节律表达的影响，我们期望 建立一种检测方法，在药物治疗前预先筛查患者的锂反应性，并在未来 研究，剖析双相情感障碍的机制，特别是从锂的角度 敏感性和昼夜节律的产生。该模型和测定系统也应该适用于中等到 高通量筛选治疗锂反应性和耐药性双相情感障碍患者的新药 紊乱。