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

基本信息

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
项目类别：
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

项目摘要

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（由应用程序提供）：在以前的资助期间，我们证明了胚胎神经系统中的有条件消除糖原合酶激酶3S（GSK-3S），A和»，导致神经元祖稳态的明显失调。由于在临床实践中使用GSK-3抑制剂锂的使用宽度，因此该结果具有重要的翻译意义。我们假设GSK-3的灭活使祖细胞无法应对通常调节径向祖细胞转化为神经元和中间神经元前体（INP）的细胞外信号。现在，我们提出了确定的小鼠遗传实验，以评估该GSK-3调节的机制（AIM I和II）。此外，我们将使用一种化学遗传学方法来确定GSK-3缺乏祖细胞中GSK-3活性是否会导致神经发生的增强（AIM III）。最后，我们将询问GSK-3信号传导是否调节成年齿状回（AIM IV）中的神经元素。这项工作将揭示GSK-3调节哺乳动物中神经祖细胞的功能潜力和机制。这项工作还将提供有关锂在临床实践中常用的药物（越来越多的儿童）的药物的先前未识别的潜在影响的信息。最后，我们的结果可能提出了在神经元移植中扩展神经元祖细胞种群的新方法。公共卫生相关性：我们建议特定的蛋白GSK-3是神经元干细胞的主要调节剂。 GSK-3的这种功能需要研究，因为GSK-3抑制剂锂通常用于临床实践，越来越多地用于儿童。我们的结果还可能提出在神经元移植中扩展神经元干细胞的新方法