Regulation of Neurogenesis and Behavior by GSK-3

GSK-3 对神经发生和行为的调节

• 批准号: 8791140
• 负责人: PETER S KLEIN
• 金额: $ 45.21万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8791140
• 关键词: Accounting; Address; Adjuvant; Adult; Adverse effects; Affect; Antidepressive Agents; Behavior; Behavior Disorders; Behavioral; Behavioral Assay; Bipolar Depression; Bipolar Disorder; Brain; Clinical; Collaborations; Complex; Data; Development; Disease; Feedback; Future; Gene Targeting; Genetic; Glycogen Synthase Kinase 3; Goals; Health; Hippocampus (Brain); Homeostasis; Human Biology; Knock-out; Lead; Learning; Lithium; Mediating; Molecular; Molecular Target; Mood Disorders; Mood stabilizers; Moods; Mus; Neurons; Oxygen; Oxygen measurement, partial pressure, arterial; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Play; Population; Regulation; Research; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Therapeutic Effect; Tissues; Work; base; behavioral response; cell type; cellular targeting; common treatment; hypoxia inducible factor 1; improved; in vivo; inhibitor/antagonist; insight; loss of function; nerve stem cell; neurogenesis; neurotrophic factor; new therapeutic target; novel; novel strategies; novel therapeutics; research study; response; synaptogenesis; transcription factor; treatment-resistant depression

DESCRIPTION (provided by applicant): Bipolar disorder (BD) is a debilitating mood disorder that affects 1-2% of the population. Lithium is highly effective in BD, but the molecular mechanism that underlies the therapeutic response is unknown. Defining the cellular and molecular targets of lithium in the adult brain will be crucial to understanding the factors that contribute to this complex disorder. We have advanced the hypothesis that lithium acts on mammalian behavior and mood disorders through inhibition of glycogen synthase kinase-3 (GSK-3), a central regulator of multiple signaling pathways. The goals of the work proposed here are to establish how cellular and molecular responses to GSK-3 inhibition relate to the therapeutic response in BD, with a long-term goal to understand the molecular basis of affective disorders and to discover new therapeutic targets in BD and other affective disorders. This proposal describes experiments to define the signaling mechanisms that account for the effects of lithium on neural stem cell homeostasis and behavior. Our working hypothesis is that GSK-3 modulates both behavior and neurogenesis through interaction with Wnt signaling and oxygen sensing pathways. In addition, we hypothesize that GSK-3 is highly regulated by positive feedback circuits that can be targeted for the development of new therapeutic strategies in affective disorders. In aim 1, we will test whether Wnt signaling is required for the effects of lithium in either neurogenesis or behavior. We will also test whether neurogenesis is required for behavioral responses to lithium using a genetic strategy to target NSPCs in the adult hippocampus. Aim 2 addresses a new connection between oxygen sensing and the Wnt pathway, a major target of GSK-3 and a regulator of neurogenesis. We will explore the role of hypoxia inducible factor 1 (HIF-1) in the regulation of neurogenesis and lithium-sensitive behaviors and investigate the role of HIF-1 target genes in the response to lithium. In aim 3 we will explore a novel mechanism for the enhancement of GSK-3 inhibition by lithium and investigate approaches to perturb GSK-3 regulatory circuits as potentially new therapeutic targets in the treatment of BD and other affective disorders. These studies should provide a better understanding of the molecular and cellular mechanisms that underlie BD and the response to therapy and should lead to new approaches to the treatment of this common and devastating affective disorder.

描述（由申请人提供）：躁郁症 (BD) 是一种使人衰弱的情绪障碍，影响 1-2% 的人口。锂对于双相情感障碍非常有效，但治疗反应的分子机制尚不清楚。确定成人大脑中锂的细胞和分子靶标对于理解导致这种复杂疾病的因素至关重要。我们提出了这样的假设：锂通过抑制糖原合酶激酶 3 (GSK-3)（多种信号传导途径的核心调节因子）来影响哺乳动物的行为和情绪障碍。这里提出的工作目标是确定对 GSK-3 抑制的细胞和分子反应如何与 BD 的治疗反应相关，长期目标是了解情感障碍的分子基础并发现 BD 的新治疗靶点和其他情感障碍。该提案描述了定义信号机制的实验，该机制解释了锂对神经干细胞稳态和行为的影响。我们的工作假设是 GSK-3 通过与 Wnt 信号传导和氧传感通路相互作用来调节行为和神经发生。此外，我们假设 GSK-3 受到正反馈回路的高度调节，可用于开发情感障碍的新治疗策略。在目标 1 中，我们将测试 Wnt 信号传导是否是锂对神经发生或行为的影响所必需的。我们还将使用针对成人海马中 NSPC 的遗传策略来测试对锂的行为反应是否需要神经发生。目标 2 解决了氧传感与 Wnt 通路之间的新联系，Wnt 通路是 GSK-3 的主要靶标和神经发生的调节因子。我们将探讨缺氧诱导因子1（HIF-1）在神经发生和锂敏感行为调节中的作用，并研究HIF-1靶基因在锂反应中的作用。在目标 3 中，我们将探索锂增强 GSK-3 抑制的新机制，并研究扰乱 GSK-3 调节回路的方法，作为治疗双相情感障碍和其他情感障碍的潜在新治疗靶点。这些研究应该可以更好地理解双相情感障碍的分子和细胞机制以及对治疗的反应，并应该带来治疗这种常见和毁灭性情感障碍的新方法。