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）：双相情感障碍（BD）是一种使人衰弱的情绪障碍，影响了1-2％的人口。锂在BD中是非常有效的，但是基于治疗反应的分子机制尚不清楚。定义成年大脑中锂的细胞和分子靶标对于理解有助于这种复杂疾病的因素至关重要。我们提出了这样的假设，即锂通过抑制糖原合酶激酶3（GSK-3）（GSK-3）的糖原行为和情绪障碍作用，这是多个信号通路的中心调节剂。这里提出的工作的目标是确定对GSK-3抑制的细胞和分子反应如何与BD的治疗反应有关，其长期目标是了解情感障碍的分子基础，并发现BD中的新治疗靶点和其他情感障碍。该提案描述了定义锂对神经干细胞稳态和行为影响的信号传导机制的实验。我们的工作假设是，GSK-3通过与Wnt信号传导和氧气传感途径相互作用来调节行为和神经发生。此外，我们假设GSK-3受到积极反馈电路的高度调节，这些反馈电路可以针对发展情感障碍的新治疗策略。在AIM 1中，我们将测试锂在神经发生或行为中是否需要Wnt信号传导。我们还将使用遗传策略来靶向成人海马中的NSPC是否需要神经发生对锂的行为反应。 AIM 2解决了氧气传感与Wnt途径之间的新联系，Wnt途径是GSK-3的主要目标和神经发生的调节剂。我们将探讨缺氧诱导因子1（HIF-1）在调节神经发生和锂敏感行为中的作用，并研究HIF-1靶基因在对锂反应的反应中的作用。在AIM 3中，我们将探索一种新型的机制，用于通过锂来增强GSK-3抑制作用，并研究扰动GSK-3调节回路的方法，作为在BD和其他情感障碍治疗中潜在的新治疗靶标。这些研究应更好地理解BD和对治疗的反应的分子和细胞机制，并应为治疗这种常见和毁灭性情感障碍提供新的方法。