Regulation of Neurogenesis and Behavior by GSK-3

GSK-3 对神经发生和行为的调节

• 批准号: 8652557
• 负责人: PETER S KLEIN
• 金额: $ 52.06万
• 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/8652557
• 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; Hippocampus (Brain); Homeostasis; Human Biology; Knock-out; Lead; Learning; Lithium; Mediating; Mental Depression; 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; Resistance; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Therapeutic Effect; Tissues; Work; base; 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; public health relevance; research study; response; synaptogenesis; transcription factor

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.

双相情感障碍（BD）是一种使人衰弱的情绪障碍，影响人群的1-2％。锂是高度的 在BD中有效，但是基于治疗反应的分子机制尚不清楚。定义 成人大脑中锂的细胞和分子靶标对于理解因素至关重要 有助于这种复杂的疾病。我们提出了锂作用于哺乳动物的假设 通过抑制糖原合酶激酶-3（GSK-3）的行为和情绪障碍，这是一个中心调节剂 多个信号通路。这里提出的工作的目标是确定细胞和分子如何 对GSK-3抑制的反应与BD中的治疗反应有关，其长期目标是了解 情感障碍的分子基础，并在BD和其他情感中发现新的治疗靶标 疾病。该提案描述了定义造成影响的信号传导机制的实验 锂的神经干细胞稳态和行为。我们的工作假设是GSK-3调节 通过与Wnt信号传导和氧气传感途径相互作用，行为和神经发生。在 此外，我们假设GSK-3受到正面反馈电路的高度调节，可以针对 在情感障碍中发展新的治疗策略。在AIM 1中，我们将测试是否wnt 锂在神经发生或行为中的作用需要信号传导。我们还将测试是否 使用遗传策略靶向NSPC，需要神经发生对锂的行为反应需要 成人海马。 AIM 2解决了氧气传感与Wnt途径之间的新联系 GSK-3的主要靶标和神经发生的调节剂。我们将探索缺氧诱导因子1的作用1 （HIF-1）在调节神经发生和锂敏感行为中，并研究了HIF-1的作用 靶基因对锂的反应。在AIM 3中，我们将探索一种增强的新型机制 GSK-3通过锂抑制并调查GSK-GSK-3调节回路的方法可能是新的 治疗BD和其他情感障碍的治疗靶标。这些研究应该更好 理解BD基础的分子和细胞机制以及对治疗的反应和 应该为治疗这种常见和毁灭性情感障碍的新方法提供新的方法。