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：
8212516
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/8212516
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（由申请人提供）：在之前的资助期间，我们证明了糖原合成酶激酶-3s (GSK-3s)、a 和 ¿ ，在胚胎神经系统中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，我们发现 GSK-3 的失活会导致祖细胞丧失能力。我们现在明确提出了小鼠遗传实验来评估这种机制。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）。 GSK-3 信号调节成年齿状回中的神经祖细胞（目标 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。还提供了有关锂的潜在影响的信息，锂是临床实践中常用的药物，尤其是在儿童中。最后，我们的结果可能会提出在神经移植中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剂，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，并且越来越多地用于临床实践。我们的结果还可能为在神经移植中扩增神经干细胞提供新的方法。