GSK-3 Signaling: Targeting Actions of Mood Stablizing

GSK-3 信号传导：稳定情绪的目标作用

• 批准号: 6824397
• 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/6824397
• 关键词: O glycosidase; brain; disease /disorder model; drug screening /evaluation; enzyme mechanism; ethology; genetically modified animals; human tissue; kinase inhibitor; laboratory mouse; lithium; mental disorder chemotherapy; mood disorders; pharmacokinetics; proteomics; serine threonine protein kinase; transcription factor; valproate

Glycogen synthase kinase-3 (GSK-3), is directly inhibited by lithium, and as such is an interesting candidate as a potential target for novel therapeutics. There is tremendous interest in GSK-3 inhibitors as novel therapeutic agents, and selective, small molecule compounds are rapidly being developed for a broad range of maladies including diabetes, Alzheimer's disease, stroke, and inflammation. With convincing preclinical evidence, it is likely that those medications developed will be utilized in bipolar disorder trials. Although GSK-3 was identified as in vitro target of lithium in 1996, the degree of inhibition of this enzyme in the adult mammalian brain at therapeutically relevant concentrations has not been established and was an impediment to future bipolar disorder trials directed at GSK-3 inhibition. In a manuscript currently in press in Neuropsychopharmacology, we showed, using subcellular fractionation and real-time PCR, that treatment with lithium and valproic acid at therapeutic serum concentrations postranslationally regulates ?O-catenin (a GSK-3 target and important transcription factor) in the rat brain, suggesting that lithium significantly inhibits brain GSK-3 in vivo at concentrations relevant for the treatment of bipolar disorder. The finding that two structurally dissimilar mood-stabilizing medications exert similar effects on ?O-catenin, suggests a possible importance of this protein in the treatment of bipolar disorder. To further address importance of this transcription factor, I am collaborating with Charles Eberhart (Johns Hopkins University) to investigate the behavioral and biochemical manifestations of over-expression of ?O-catenin in the adult brain of transgenic mice. Additional studies currently underway plan to access the effects of novel, specific, GSK-3 inhibitors in rodent behavioral models. It is exciting that this work may help facilitate clinical trials. However, a major concern in the development of GSK-3 inhibitors has been that the Wnt signaling pathway!Vof which GSK-3 is an important intermediary molecule!Vis implicated in many human cancers. We therefore investigated, and recently published in Pharmacological Research, a manuscript describing the effects of lithium in a murine model predisposed to the formation of tumors of the Wnt pathway!Xthe adenomatous polyposis coli (APC) mouse; we found that 60 days of lithium treatment did not increase the number of tumors. Similar studies to our own APC mouse experiments will be critical for establishing the safety of novel GSK-3 inhibitors prior to use in humans. In addition to the studies designed to understand the role of GSK-3 in bipolar disorder pathophysiology and treatment, we are also assessing the effects of mood stabilizer treatments in a line of mice containing a CRE-?O galactosidase reporter construct (through a collaboration with Daniel Storm, University of Washington). Both lithium and valproic acid have been shown by our group to increase the levels of the activated form of CREB; the results of these studies with CRE-?O galactosidase reporter mice may provide more evidence for this observation, in addition to providing a greater degree of regional and temporal specificity.

糖原合酶激酶 3 (GSK-3) 直接被锂抑制，因此是一种有趣的候选药物，作为新型疗法的潜在靶点。人们对 GSK-3 抑制剂作为新型治疗剂产生了极大的兴趣，并且正在迅速开发选择性小分子化合物来治疗多种疾病，包括糖尿病、阿尔茨海默病、中风和炎症。有了令人信服的临床前证据，这些开发的药物很可能将用于双相情感障碍试验。尽管 GSK-3 于 1996 年被确定为锂的体外靶点，但该酶在成年哺乳动物大脑中在治疗相关浓度下的抑制程度尚未确定，并且阻碍了未来针对 GSK-3 抑制的双相情感障碍试验。在《神经精神药理学》目前发表的一篇手稿中，我们使用亚细胞分级分离和实时 PCR 表明，在治疗血清浓度下用锂和丙戊酸治疗可在翻译后调节 ?O-连环蛋白（GSK-3 靶标和重要的转录因子）。大鼠大脑，表明锂在与治疗双相情感障碍相关的浓度下显着抑制体内大脑 GSK-3。两种结构不同的情绪稳定药物对 β-连环蛋白具有相似的作用，这一发现表明这种蛋白质在双相情感障碍的治疗中可能具有重要意义。为了进一步阐明这种转录因子的重要性，我与 Charles Eberhart（约翰·霍普金斯大学）合作，研究转基因小鼠成年大脑中 β-连环蛋白过度表达的行为和生化表现。目前正在进行的其他研究计划了解新型、特异性 GSK-3 抑制剂在啮齿动物行为模型中的作用。 令人兴奋的是，这项工作可能有助于促进临床试验。然而，GSK-3抑制剂开发中的一个主要问题是Wnt信号通路（其中GSK-3是重要的中间分子）与许多人类癌症有关。因此，我们研究了一份手稿，最近发表在《药理学研究》上，该手稿描述了锂对易形成 Wnt 通路肿瘤的小鼠模型的影响！X 腺瘤性结肠息肉病 (APC) 小鼠；我们发现60天的锂治疗并没有增加肿瘤的数量。与我们自己的 APC 小鼠实验类似的研究对于在人类使用之前确定新型 GSK-3 抑制剂的安全性至关重要。 除了旨在了解 GSK-3 在双相情感障碍病理生理学和治疗中的作用的研究之外，我们还评估了情绪稳定剂治疗对含有 CRE-αO 半乳糖苷酶报告基因构建体的小鼠系的影响（通过与丹尼尔·斯托姆，华盛顿大学）。我们的团队已证明锂和丙戊酸都可以提高 CREB ​​活性形式的水平；这些使用 CRE-αO 半乳糖苷酶报告小鼠的研究结果除了提供更大程度的区域和时间特异性之外，还可以为这一观察结果提供更多证据。