Testing whether the enzyme GSK-3 is a therapeutically re

测试 GSK-3 酶是否具有治疗作用

• 批准号: 6984237
• 负责人: HUSSEINI K MANJI
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 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/6984237
• 关键词: antidepressants; behavior test; bipolar depression; cadherins; enzyme inhibitors; genetically modified animals; immunocytochemistry; laboratory mouse; lithium; mental disorder chemotherapy; neuroregulation; serine threonine protein kinase

The mood stabilizer lithium inhibits a select group of enzymes, including glycogen synthase kinase-3 (GSK-3). However, it is unclear if lithium!|s inhibition of GSK-3 is relevant for its antimanic and antidepressant effectiveness. We are utilizing biochemical, cellular, histochemical, genomic, and behavioral validation approaches. One of the primary targets of GSK-3 is the transcription factor fO-catenin and we have showed that lithium administration to rats, in a clinically relevant paradigm, results in an increase in fO-catenin levels. Using gene array technology, we are studying the transcription profile of fO-catenin up-regulation in the central nervous system. We are additionally studying the effects of ?O-catenin up-regulation on the generation of new neurons, a process referred to as neurogenesis that has been linked to the actions of antidepressant medications. We additionally are utilizing of rodent behavioral models, and two distinct but complementary approaches (pharmacologic inhibition and transgenic gene expression) to attempt to further validate GSK-3 as a possible mediator of lithium!|s therapeutic effects. Using both approaches, we have found the rodents exhibit both antidepressant-like and antimanic-like behavior. Combined, these data support the hypothesis that lithium may exert its antidepressant and antimanic effects through inhibition of GSK-3, and that novel small-molecule GSK-3 inhibitors may represent a truly novel class of medications useful for the treatment of bipolar disorder and depression. Ultimate validation of lithium!|s therapeutic target will require clinical trials with novel inhibitors. In this regard, GSK-3 inhibitors are being developed by industry.

情绪稳定剂锂能抑制一组特定的酶，包括糖原合成酶-3(GSK-3)。然而，尚不清楚锂！|S抑制葛兰素史克-3是否与其抗躁狂和抗抑郁效果有关。我们正在利用生化、细胞、组织化学、基因组和行为验证方法。 GSK-3的主要靶点之一是fo-catenin转录因子，我们已经证明，在临床相关的范例中，给大鼠服用锂会导致fo-catenin水平的增加。利用基因芯片技术，我们正在研究中枢神经系统中fo-catenin上调的转录图谱。此外，我们还在研究O-连环蛋白上调对新神经元生成的影响，这一过程被称为神经发生，与抗抑郁药物的作用有关。 此外，我们还利用啮齿动物行为模型和两种截然不同但互为补充的方法(药物抑制和转基因基因表达)，试图进一步验证GSK-3作为锂！|S治疗效果的可能介体。 使用这两种方法，我们发现啮齿动物既表现出抗抑郁药样行为，也表现出抗躁狂样行为。综上所述，这些数据支持锂可能通过抑制GSK-3发挥其抗抑郁和抗躁狂作用的假设，以及新型小分子GSK-3抑制剂可能代表着一类真正有助于治疗双相情感障碍和抑郁症的新型药物。锂的最终验证！|S的治疗目标将需要新型抑制剂的临床试验。在这方面，GSK-3抑制剂正在被工业界开发。