Regulation of GSK3beta by Mood Stabilizers

情绪稳定剂对 GSK3beta 的调节

• 批准号: 6838806
• 负责人: XIAOHUA LI
• 金额: $ 7.25万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-05 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6838806
• 关键词: anticonvulsants; biological signal transduction; bipolar depression; brain; cAMP response element binding protein; gel mobility shift assay; glutamates; laboratory mouse; lithium; lymphocyte; mental disorder chemotherapy; neurotransmitter transport; psychopharmacology; serine threonine protein kinase; valproate

DESCRIPTION (provided by applicant): Bipolar disorder is a severe mental disorder with limited pharmacological treatment because the pathophysiology of this severe mental illness is poorly understood. No definitive mechanism of action of available mood stabilizers has been identified, which limits the development of new mood stabilizing agents. Extensive studies in vitro and in cultured cells have shown that lithium and valproate modulate glycogen synthase kinase-3beta (GSK3beta), a unique protein kinase that is under inhibitory control by several signaling systems. Although GSK3beta is a prime candidate therapeutic target of mood stabilizers, there is limited evidence of in vivo regulation of GSK3beta by mood stabilizers, and its relevance to the therapeutic effects of mood stabilizers in bipolar disorder remains to be established. The objective of this project is to identify the in vivo regulatory effects of the available mood stabilizers on GSK3beta and the associated signaling systems, specifically the upstream PI3K/Akt signaling pathway and the downstream target transcription factor CREB. The central hypothesis for the proposed research is that GSK3beta is a central component of the mechanisms of action of lithium and other mood stabilizers in vivo. The Specific Aim of this two-year project is to test the hypothesis that lithium and other anticonvulsant mood stabilizers modulate GSK3beta in the brain and in peripheral lymphocytes of mice. The working hypotheses include that chronic treatments with therapeutically relevant doses of lithium, valproate, and lamotrigine inhibit GSK3beta in mouse brain, the mechanisms of action of the mood stabilizers may involve regulating GSK3beta or the PI3K/Akt signaling pathway, with a common consequence of regulating the transcription factor CREB, and the effect of lamotrigine on GSK3beta may be related to its blocking effects on glutamate release. If GSK3beta represents an important therapeutic target of mood stabilizers, it is important to test if changes occurring in mouse brain are also detectable in mouse lymphocytes, since this will be a basis for future testing of similar changes in humans. This study will apply knowledge obtained from in vitro studies of GSK3beta to in vivo studies of mouse brain, and for the first time proposes to identify the in vivo actions of mood stabilizers on GSK3beta and the associated PI3K/Akt signaling pathway as potential therapeutic targets of mood stabilizers. The proposed research is expected to provide significant new insight into the pathophysiology and treatment of bipolar disorder. The data obtained from this proposal will be used to support a future R01 grant application to achieve our long-term goal of understanding the pathophysiology and improving the treatment of bipolar disorder.

描述（由申请人提供）：躁郁症是一种严重的精神障碍，药理学治疗有限，因为这种严重精神疾病的病理生理学知之甚少。尚未确定可用情绪稳定器的作用机制，这限制了新的情绪稳定剂的发展。在体外和培养细胞中进行的广泛研究表明，锂和丙丙酸酯调节糖原合酶激酶-3BETA（GSK3BETA），这是一种独特的蛋白激酶，通过多个信号系统在抑制性控制下进行抑制。尽管GSK3BETA是情绪稳定剂的主要候选治疗靶点，但有限的证据表明，情绪稳定器对GSK3BETA进行了体内调节，并且与情绪稳定剂在双相情感障碍中的治疗效应相关的相关性仍然有限。该项目的目的是确定可用情绪稳定剂对GSK3BETA和相关信号系统的体内调节效应，特别是上游PI3K/AKT信号传导途径和下游目标转录因子CREB。拟议研究的中心假设是GSK3Beta是锂和其他情绪稳定剂在体内作用机理的核心组成部分。这个为期两年的项目的具体目的是检验以下假设：锂和其他抗惊厥情绪稳定剂调节大脑中的GSK3Beta和小鼠周围淋巴细胞中的GSK3Beta。工作假设包括锂，丙丙酸酯和lamotrigine的治疗相关剂量的长期治疗方法抑制了小鼠脑中的GSK3BETA，情绪稳定剂的作用机制可能涉及调节GSK3BETA或PI3K/AKT信号途径的常见效果的gsk3beta或cre the cre的效果，并具有常见的效果。 GSK3BETA上的拉莫三嗪可能与其对谷氨酸释放的封闭作用有关。如果GSK3BETA代表了情绪稳定剂的重要治疗靶标，那么重要的是要在小鼠淋巴细胞中检测到小鼠脑中发生的变化是否也可以检测到，因为这将是对人类类似变化的未来测试的基础。这项研究将应用从GSK3BETA的体外研究获得的知识对小鼠脑的体内研究，并首次提议确定情绪稳定剂对GSK3BETA和相关的PI3K/AKT信号通路的体内作用，作为情绪稳定器的潜在治疗靶标。拟议的研究预计将为双相情感障碍的病理生理学和治疗提供重大的新见解。从该提案中获得的数据将用于支持未来的R01赠款应用，以实现我们了解病理生理学并改善双相情感障碍治疗的长期目标。