GSK3: Neural Modulators and Mood Disorders

GSK3：神经调节剂和情绪障碍

• 批准号: 7030466
• 负责人: XIAOHUA LI
• 金额: $ 24.74万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7030466
• 关键词: amphetamines; anticonvulsants; antipsychotic agents; behavioral /social science research tag; brain metabolism; enzyme activity; glucocorticoids; glutamates; immunocytochemistry; laboratory mouse; lithium; mood disorders; neurochemistry; neuroregulation; psychopathology; psychopharmacology; psychotropic drugs; serine threonine protein kinase; serotonin inhibitor; valproate; western blottings

DESCRIPTION (provided by applicant): Mood disorders, including bipolar disorder and depressive disorder, are severe mental illnesses that directly affect over 20% of individuals in the U.S. The pathophysiology of mood disorders is poorly understood, and the treatment options are therefore limited. The long term goal of our research is to understand the pathophysiology and improve the treatment of mood disorders. The objective of this application is to identify a central molecular target in animal brain that is regulated by neural modulators relevant to mood disorders. Based on the accumulating evidence showing that glycogen synthase kinase-3 (GSK3) is an active and highly regulated protein kinase in neural tissues, GSK3 is an intracellular target of neurotrophins involved in mood disorders, the mood stabilizer lithium inhibits GSK3, and we have recently discovered that serotonin, a major mood disorder-related monoamine neurotransmitter, regulates GSK3 in animal brain, we hypothesize that GSK3 is a major protein kinase which activity can be altered by various neural modulators involved in the development and the treatment of mood disorders. Three specific aims will be pursued to test the central hypothesis: Specific Aim 1 will test the hypothesis that mood stabilizing agents, including lithium, divalproate, and lamotrigine, regulate GSK3 in mouse brain through different mechanisms of action. Specific Aim 2 will test the hypothesis that serotonergic modulators used in mood disorders, including serotonin reuptake inhibitor antidepressants and dual-acting antipsychotics, regulate GSK3 in mouse brain. Specific Aim 3 will test the hypothesis that GSK3 activity is abnormally regulated by altered brain activities that simulate what occur in mood disorders, which can be prevented or reversed by mood disorder treatments. These studies will thus use straightforward strategies to conduct clinically relevant research in mood disorders. The proposed research is innovative because it aims to identify the in vivo regulation of GSK3 by various neural modulators relevant to the development and the treatment of mood disorders, which have not to date been thoroughly investigated. This research is expected to provide significant new insight into the pathophysiology and the treatment of mood disorders.

描述（由申请人提供）：情绪障碍，包括双相情感障碍和抑郁症，是严重的精神疾病，直接影响美国20％以上的患者，人们对情绪障碍的病理生理学的了解很少，因此治疗方案受到限制。我们研究的长期目标是了解病理生理学并改善情绪障碍的治疗方法。该应用的目的是确定动物大脑中的中央分子靶标，该靶标受与情绪障碍相关的神经调节剂调节。 Based on the accumulating evidence showing that glycogen synthase kinase-3 (GSK3) is an active and highly regulated protein kinase in neural tissues, GSK3 is an intracellular target of neurotrophins involved in mood disorders, the mood stabilizer lithium inhibits GSK3, and we have recently discovered that serotonin, a major mood disorder-related monoamine neurotransmitter,调节动物脑中的GSK3，我们假设GSK3是一种主要的蛋白激酶，可以通过参与情绪障碍发展和治疗的各种神经调节剂来改变活性。将追求三个特定的目标来检验中心假设：具体目标1将检验以下假设：锂，脱甲酸和拉莫三嗪在内的情绪稳定剂，通过不同的作用机理来调节小鼠大脑中的GSK3。具体目标2将检验以下假设：血清素能调节剂用于情绪障碍，包括血清素再摄取抑制剂抗抑郁药和双作用抗精神病药，调节小鼠大脑中的GSK3。具体目标3将检验以下假设：GSK3活性受到改变的大脑活动的调节，该活动模拟了情绪障碍中发生的事情，这可以通过情绪障碍治疗来预防或反转。因此，这些研究将使用直接的策略来进行情绪障碍的临床相关研究。拟议的研究具有创新性，因为它旨在确定与与情绪障碍的发展和治疗相关的各种神经调节剂对GSK3的体内调节，这些神经调节剂迄今尚未对情绪障碍的发展和治疗进行彻底研究。预计这项研究将为病理生理学和情绪障碍的治疗提供重大的新见解。