GSK-3 is a Master Regulator of Neural Progenitor Self-Renewal

GSK-3 是神经祖细胞自我更新的主要调节因子

• 批准号: 8017363
• 负责人: WILLIAM D SNIDER
• 金额: $ 39.35万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8017363
• 关键词: Adult; Alleles; Brain; Breeding; CCI-779; Cell Count; Cell Cycle; Cell Proliferation; Chemicals; Child; Development; Dorsal; Embryo; Embryonic Nervous System; Erinaceidae; Exhibits; Family member; Funding; Genetic; Genetic Recombination; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Hippocampus (Brain); Homeostasis; Investigation; Knock-in Mouse; Life; Lithium; Mammals; Mediating; Mediator of activation protein; Mus; Mutagenesis; Neuronal Differentiation; Neurons; Notch Signaling Pathway; Pharmaceutical Preparations; Phosphotransferases; Point Mutation; Population; Positioning Attribute; Proteins; Radial; Receptor Protein-Tyrosine Kinases; Regulation; Signal Transduction; Sirolimus; Stem cells; Telencephalon; Testing; Transplantation; Work; cell type; cellular imaging; chemical genetics; clinical practice; dentate gyrus; extracellular; granule cell; in vivo; inhibitor/antagonist; nerve stem cell; nestin protein; neurogenesis; notch protein; postnatal; progenitor; public health relevance; relating to nervous system; research study; self-renewal

DESCRIPTION (provided by applicant): In the prior funding period, we demonstrated that conditional elimination of the Glycogen Synthase Kinase-3s (GSK-3s), a and ¿, in the embryonic nervous system results in remarkable dysregulation of neural progenitor homeostasis. This result has important translational significance because of the widespread use of a GSK-3 inhibitor, lithium, in clinical practice. We hypothesize that inactivation of GSK-3s renders progenitors incapable of responding to the extracellular signals that normally regulate conversion of radial progenitors to neurons and intermediate neuronal precursors (INPs). We now propose definitive mouse genetic experiments to assess mechanisms of this GSK-3 regulation (Aims I and II). Further, we will use a chemical genetics approach to determine if reinduction of GSK-3 activity in GSK-3 deficient progenitors will result in enhanced neurogenesis (Aim III). Finally we will ask whether GSK-3 signaling regulates neural progenitors in the adult dentate gyrus (Aim IV). This work will reveal the functional potential and mechanisms of GSK-3 regulation of neural progenitors in mammals. The work will also provide information on previously unrecognized potential effects of lithium a drug commonly used in clinical practice, increasingly in children. Finally our results may suggest new ways to expand neural progenitor populations in the setting of neural transplantation. PUBLIC HEALTH RELEVANCE: We propose that a specific protein, GSK-3, is a master regulator of neural stem cells. This function of GSK-3 requires investigation because a GSK-3 inhibitor, lithium, is commonly used in clinical practice, increasingly in children. Our results may also suggest new ways to expand neural stem cells in the setting of neural transplantation

描述（由申请人提供）：在之前的资助期间，我们证明了胚胎神经系统中糖原合酶激酶-3s (GSK-3s)、a 和 ¿ 的有条件消除会导致神经祖细胞稳态的显着失调。由于 GSK-3 抑制剂锂在临床实践中的广泛使用，这一结果具有重要的转化意义。我们假设 GSK-3 失活使祖细胞无法对通常调节径向祖细胞向神经元和中间神经元前体 (INP) 转化的细胞外信号做出反应。我们现在提出明确的小鼠遗传实验来评估 GSK-3 调节的机制（目标 I 和 II）。此外，我们将使用化学遗传学方法来确定 GSK-3 缺陷祖细胞中 GSK-3 活性的重新诱导是否会导致神经发生增强（目标 III）。最后我们将询问 GSK-3 信号传导是否调节成人齿状回的神经祖细胞 (Aim IV)。这项工作将揭示 GSK-3 调节哺乳动物神经祖细胞的功能潜力和机制。这项工作还将提供有关锂的潜在影响的信息，锂是临床实践中常用的药物，越来越多地用于儿童。最后，我们的结果可能会提出在神经移植的情况下扩大神经祖细胞群的新方法。 公共健康相关性：我们认为一种特定的蛋白质 GSK-3 是神经干细胞的主要调节因子。 GSK-3 的这种功能需要进行研究，因为 GSK-3 抑制剂锂在临床实践中常用，尤其是在儿童中使用。我们的结果还可能提出在神经移植中扩增神经干细胞的新方法