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.

情绪稳定剂锂会抑制一组选定的酶，包括糖原合成酶激酶 3 (GSK-3)。然而，尚不清楚锂对 GSK-3 的抑制是否与其抗躁狂和抗抑郁功效相关。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 的主要靶标之一是转录因子 fO-连环蛋白，我们已经证明，在临床相关范例中，给大鼠施用锂会导致 fO-连环蛋白水平增加。利用基因阵列技术，我们正在研究中枢神经系统中 fO-catenin 上调的转录谱。我们还在研究 β-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。 我们还利用啮齿动物行为模型和两种不同但互补的方法（药理学抑制和转基因基因表达）来尝试进一步验证 GSK-3 作为锂治疗效果的可能介质。 使用这两种方法，我们发现啮齿动物表现出抗抑郁样和抗躁狂样行为。综合起来，这些数据支持这样的假设：锂可能通过抑制 GSK-3 发挥其抗抑郁和抗躁狂作用，并且新型小分子 GSK-3 抑制剂可能代表一类真正新颖的药物，可用于治疗双相情感障碍和抑郁症。锂治疗靶点的最终验证需要使用新型抑制剂进行临床试验。对此，业界正在开发GSK-3抑制剂。