Effects of lithium on cellular signaling

锂对细胞信号传导的影响

• 批准号: 8247461
• 负责人: RICHARD S. JOPE
• 金额: $ 38.04万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-02-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8247461
• 关键词: Address; Adolescent; Adult; Alanine; Alzheimer' s Disease; Amphetamines; Antidepressive Agents; Autopsy; Behavior; Behavioral; Behavioral Genetics; Biochemical; Bipolar Disorder; Brain; Cells; Central Nervous System Diseases; Chronic; Chronic stress; Development; Disease; Etiology; Exercise; Figs - dietary; Fragile X Syndrome; Genetic; Glycogen Synthase Kinase 3; Goals; Human; Hyperactive behavior; Individual; Inflammation; Inflammatory; Intervention; Journals; Ketamine; Laboratory Finding; Link; Lithium; Mental Depression; Mood Disorders; Mood stabilizers; Moods; Mus; Mutate; Mutation; Neurodegenerative Disorders; Neuromodulator; Outcome; Peripheral; Pharmaceutical Preparations; Phenotype; Phosphorylation; Physiological; Population; Predisposition; Prevalence; Productivity; Protein Isoforms; Publications; Research Design; Research Personnel; Role; Serine; Serotonin; Signal Pathway; Signal Transduction; Stress; Stroke; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Transgenic Mice; United States; behavior measurement; behavior test; behavioral impairment; environmental enrichment for laboratory animals; enzyme activity; experience; improved; inhibitor/antagonist; innovation; interest; mood regulation; mutant; neurogenesis; neurotrophic factor; novel; protein complex; response; restraint stress; therapeutic target; treatment response

DESCRIPTION (provided by applicant): The etiology of mood disorders is unknown, a critical problem considering their lifetime prevalence of ~20%. Many studies support a role of dysregulated GSK3 in contributing to mood disorders including studies of human postmortem brain, peripheral cells, and genetics, and behavioral studies in glycogen synthase kinase-3 (GSK3) transgenic mice and with GSK3 inhibitors. Lithium, the classical mood stabilizer used to treat bipolar disorder, inhibits GSK3 by a dual mechanism, directly inhibiting enzyme activity and increasing the inhibitory serine-phosphorylation of GSK3. This project will extend key findings from our current period of support that provide important links between lithium's inhibition of GSK3 and susceptibility to mood disorders in behavior, neurogenesis, signaling, and developmental studies. These topics represent novel findings by this laboratory, indicative of the innovation and productivity of this project, and significantly contribute to progress in understanding the etiology of mood disorders and mechanisms of action of therapeutic drugs that should help to develop improved interventions. Specific Aim 1 will test if serine-phosphorylation of GSK3 regulates mood-relevant behaviors. We will use isoform-selective GSK3?21A/21A/?9A/9A knockin mice, where the regulatory serine of either GSK3 isoform is mutated to alanines, for behavioral tests to clarify the regulation of mood relevant behaviors by active GSK3. Since neurogenesis may be involved in mood disorder susceptibility and/or therapeutic responses, Specific Aim 2 will test if GSK3 regulates the plasticity of neurogenesis. We will test if GSK3 knockin mice display altered neurogenesis increased by exercise and impaired by chronic stress, relate to mood-relevant behaviors, and examine mechanisms. Vulnerability to mood disorders is greatest during development. Since we found GSK3 levels are elevated several-fold in juvenile and adolescent mouse brain, the increased GSK3 may contribute to developmentally-regulated susceptibility to mood disorders. Specific Aim 3 will test mechanisms by which dysregulated GSK3 may be involved in mood-relevant behaviors and responses to therapeutic drugs. We will test if the rapid antidepressant effect of ketamine involves inhibition of GSK3, test if neurotrophins or inflammatory molecules are altered by GSK3 and associated with susceptibilities to mood-relevant behaviors and neurogenesis studied in SA1 and SA2, and examine changes in GSK3 association in protein complexes that regulate signaling. Specific Aim 4 will test the developmental profile of heightened susceptibility to depression-like behavior and hyperactivity in GSK3 knockin mice and developmental responses to drugs. Altogether, this project will continue to address important problems concerning the causes and treatments of mood disorders. PUBLIC HEALTH RELEVANCE: Mood disorders afflict approximately 20% of the population of the United States at some point in their lifetimes. However, because the underlying biochemical causes of these diseases are not known, treatments often do not adequately provide therapeutic benefits. The classical mood stabilizer lithium is an inhibitor of glycogen synthase kinase-3 (GSK3). Increasing evidence suggests this contributes to lithium's therapeutic effects and that GSK3 is dysregulated in mood disorders. This project will address potential causes of susceptibilities to mood disorders associated with dysregulated GSK3 and lithium's therapeutic effects with the aim of understanding the etiologies of mood disorders and developing better therapeutic interventions.

描述（由申请人提供）：情绪障碍的病因尚不清楚，考虑到其终生患病率约为20％，这是一个关键问题。许多研究支持GSK3失调的作用在导致情绪障碍的作用，包括对糖原合酶激酶激酶3（GSK3）转基因小鼠和GSK3抑制剂的糖原合酶激酶-3（GSK3）中的人类后脑，外周细胞和遗传学的研究以及行为研究。锂是用于治疗躁郁症的经典情绪稳定剂，通过双重机制抑制GSK3，直接抑制酶活性并增加GSK3的抑制性丝氨酸磷酸化。该项目将从我们目前的支持时期扩展关键发现，这些发现提供了锂对GSK3的抑制与对行为，神经发生，信号和发育研究中情绪障碍的敏感性之间的重要联系。这些主题代表了该实验室的新发现，这表明了该项目的创新和生产力，并在理解情绪障碍的病因和治疗药物作用机制方面有着重要的进展，这些方法应有助于发展改善干预措施。特定的目标1将测试GSK3的丝氨酸磷酸化是否调节与情绪相关的行为。我们将使用同工型选择性GSK3？21a/21a/？9a/9a敲击蛋白小鼠，其中任何一种GSK3同工型的调节性丝氨酸都被突变为丙氨酸，以阐明主动GSK3的调节情绪相关行为。由于神经发生可能与情绪障碍敏感性和/或治疗反应有关，因此特定的目标2将测试GSK3是否调节神经发生的可塑性。我们将测试GSK3敲蛋白小鼠是否显示出改变神经发生因运动而增加并因慢性压力而损害，与情绪相关的行为和检查机制有关。在发育过程中，对情绪障碍的脆弱性是最大的。由于我们发现在少年和青少年小鼠脑中GSK3水平升高了几倍，因此GSK3的增加可能导致对情绪障碍的发育调节敏感性。特定的目标3将测试与情绪相关的行为和对治疗药物的反应可能涉及的GSK3失调的机制。我们将测试氯胺酮的快速抗抑郁作用是否涉及抑制GSK3，测试神经营养蛋白或炎症分子是否因GSK3改变了，并且与对SA1和SA2中的情绪相关行为和神经发生的敏感性有关，并检查了GOSK3蛋白质复合物中的变化。具体目标4将测试GSK3敲击蛋白小鼠对抑郁症样行为和多动症的敏感性增强的发展概况以及对药物的发育反应。总之，该项目将继续解决有关情绪障碍原因和治疗方法的重要问题。 公共卫生相关性：一生中某个时候，情绪障碍折磨了美国人口的20％。但是，由于这些疾病的潜在生化原因尚不清楚，因此治疗通常不能充分提供治疗益处。经典的情绪稳定锂是糖原合酶激酶3（GSK3）的抑制剂。越来越多的证据表明，这有助于锂的治疗作用，而GSK3在情绪障碍中失调。该项目将解决与GSK3失调和锂的治疗作用相关的情绪障碍的潜在原因，目的是了解情绪障碍的病因并制定更好的治疗性干预措施。