DIFFERENTIAL IN VITRO LITHIUM RESPONSES IN BIPOLAR PATIENTS

双相情感障碍患者体外锂反应的差异

• 批准号: 8359903
• 负责人: CHIAKI FUKUHARA
• 金额: $ 8.31万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359903
• 关键词: Adverse effects; Affect; Animal Model; Biological Assay; Bipolar Disorder; Blood Cells; Brain; Cell model; Circadian Rhythms; Clinical Research; Funding; Gene Expression; Gene Proteins; Genes; Grant; Human; In Vitro; Lithium; Manic; Measurement; Mental Depression; Mental disorders; Modeling; Mood stabilizers; Moods; National Center for Research Resources; Output; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Principal Investigator; Recurrence; Research; Research Infrastructure; Resources; Role; Safety; Source; Suicide; Testing; Therapeutic; Translational Research; United States; United States National Institutes of Health; cost; improved; in vitro Assay; macrophage; peroxiredoxin 2; prevent; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Bipolar disorder, a common psychiatric disorder, is characterized by recurrent episodes of mania and depression. The mood stabilizer lithium has proven its efficacy in preventing the recurrence of mania and suicide more than any other drug for more than 50 years. In the past decade, however, lithium use in the United States has declined substantially because lithium is more difficult to use and has a low margin of safety. Only a subpopulation of bipolar patients shows benefits from lithium treatment. To improve lithium pharmacotherapy, it is beneficial to develop an in vitro assay that can be applied prior to treating patients with the drug to predict which patients will show a therapeutic response to lithium. The assay can also be used to find drugs that are as effective as lithium, applicable to all types of bipolar patients, and with fewer side effects. Because there is no cell or animal model to study differential lithium sensitivity, such assay can be used as a model to understand mechanisms how such sensitivity is controlled. Recent studies indicate that multiple genes and proteins cooperate to control pathogenesis of bipolar disorder and lithium sensitivity. Therefore, testing for differential lithium responsiveness utilizing more comprehensive parameters should be more successful in predicting lithium sensitivity. Two parameters are chosen to compare lithium sensitivity; in vitro measurements of circadian phase and peroxiredoxin 2 (PRD2) in blood cells. There is a close relation between mood status and circadian rhythm expression, and lithium has been shown to affect circadian rhythm expresion in many species, including humans. Therefore, circadain parameter is one of the promising output to evaluate the effects of lithium on moode stabilization. Another line of study has shown that bipoalr patients have neurodegenration in their brains, and lithium can fix such conditiosn. Our previous R-Center supported project identified PRD2 as a single gene that was affected by lithium stimulation. Considering PRD2' neuroprotective roles, it would be worth evaluating the effects of lithium on this gene expression between lithium responders and non-responders. In this proposal, lithium responses in these parameters will be correlated to test the hypothesis that lithium differentially affects circadian phase and PRD2 levels in macrophages of lithium-responsive and lithium-insensitive patients.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 躁郁症是一种常见的精神疾病，其特征是躁狂和抑郁症的复发发作。情绪稳定器锂已证明其在50多年来比任何其他药物都多于任何其他药物，在防止躁狂和自杀的复发方面有效。然而，在过去的十年中，美国使用锂的使用率大大下降，因为锂更难使用并且安全幅度较低。只有双极患者的亚群显示出锂治疗的好处。为了改善锂药物疗法，开发一种可以在治疗药物治疗患者以预测哪些患者对锂的治疗反应之前可以应用的体外测定是有益的。该测定法也可用于查找与锂一样有效的药物，适用于所有类型的双极患者，并且副作用较少。由于没有细胞或动物模型来研究差异锂敏感性，因此可以将这种测定用作模型，以了解机制如何控制这种敏感性。 最近的研究表明，多种基因和蛋白质合作控制双相情感障碍和锂敏感性的发病机理。因此，利用更全面参数的差异锂反应性测试应该更成功地预测锂敏感性。选择两个参数以比较锂灵敏度。血液细胞中昼夜节律和过氧蛋白2（PRD2）的体外测量。情绪状况与昼夜节律表达之间存在密切的关系，锂已被证明会影响许多物种（包括人类）的昼夜节律扩张。因此，Circadain参数是评估锂对Moode稳定的影响的有希望的输出之一。另一项研究表明，双足动物患者的大脑中有神经退行性，锂可以修复这种状态。我们以前的R-Center支持项目将PRD2识别为受锂刺激影响的单个基因。 考虑到PRD2的神经保护作用，值得评估锂对锂反应者和非反应者之间这种基因表达的影响。 在此提案中，这些参数中的锂反应将与锂反应性和对锂不敏感患者的巨噬细胞中二差差影响二十一相和PRD2水平的假设相关。