DIFFERENTIAL IN VITRO LITHIUM RESPONSES IN BIPOLAR PATIENTS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 双相情感障碍是一种常见的精神疾病，其特征是反复发作的躁狂和抑郁。50多年来，情绪稳定剂锂已被证明在预防躁狂症和自杀复发方面比任何其他药物都有效。然而，在过去的十年里，锂在美国的使用量大幅下降，因为锂更难使用，安全系数低。只有双相情感障碍患者的亚群显示出锂治疗的益处。为了改善锂药物治疗，开发一种体外测定是有益的，该测定可以在用药物治疗患者之前应用，以预测哪些患者将显示对锂的治疗反应。该检测方法也可用于寻找与锂一样有效的药物，适用于所有类型的双相情感障碍患者，副作用更少。因为没有细胞或动物模型来研究不同的锂敏感性，所以这种测定可以用作理解如何控制这种敏感性的机制的模型。 最近的研究表明，多个基因和蛋白质协同控制双相情感障碍和锂敏感性的发病机制。因此，利用更全面的参数测试不同的锂响应性在预测锂敏感性方面应该更成功。选择两个参数来比较锂敏感性;血细胞中的昼夜节律时相和过氧化物氧还蛋白2（PRD 2）的体外测量。情绪状态与昼夜节律表达之间存在密切关系，锂已被证明会影响包括人类在内的许多物种的昼夜节律表达。因此，环链参数是评价锂对情绪稳定性影响的有前景的输出之一。另一项研究表明，bipoalr患者的大脑有神经变性，锂可以修复这种情况。我们之前的R-Center支持的项目将PRD 2确定为受锂刺激影响的单个基因。 考虑到PRD 2的神经保护作用，有必要评估锂对锂应答者和无应答者之间该基因表达的影响。 在该提议中，将这些参数中的锂响应相关联，以检验锂差异地影响锂响应和锂不敏感患者的巨噬细胞中的昼夜节律时相和PRD 2水平的假设。

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.