GSK-3 as a Therapeutic Target for FASD

GSK-3 作为 FASD 的治疗靶点

基本信息

批准号：
8600487
负责人：
Lee Anna Cunningham
金额：
$ 21.25万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-05 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8600487
关键词：
Ablation Acute Adult Alzheimer&apos s Disease Behavioral Bipolar Disorder Cell Lineage Cells Clinical Collaborations Confocal Microscopy Cre-LoxP Cytoplasmic Granules Defect Development Diagnosis Ethanol Ethanol toxicity Fetal Alcohol Spectrum Disorder Fluorescence-Activated Cell Sorting Fragile X Syndrome Gene Deletion Genes Genetic Glycogen Synthase Kinase 3 Hippocampus (Brain)Intervention Label Laboratories Lead Learning Memory Metabolic Mus Neurodevelopmental Disorder Neurons Newborn Infant Pattern Preparation Publishing Relative (related person)Research Resolution Rodent Model Schizophrenia Slice Stroke Testing Therapeutic Therapeutic Effect Western Blotting adult neurogenesis alcohol exposure base enzyme activity experience fetal granule cell improved inhibitor/antagonist interest learned behavior mouse model nerve stem cell nervous system disorder nestin protein neurogenesis new therapeutic target newborn neuron novel therapeutic intervention pre-clinical prenatal exposure progenitor signal processing therapeutic target

项目摘要

Research Component 3 will investigate glycogen synthase kinase-3 (GSK-3) as a potential therapeutic target in FASD. Studies outlined in this proposal will test the hypothesis that inhibition of GSK-3 activity reverses deficits in adult hippocampal neurogenesis and associated learning behaviors in a mouse model of moderate fetal alcohol spectrum disorder (FASD). Although originally discovered as a key metabolic regulator, GSK-3 has experienced resurgence in research interest due to its ability to regulate multiple signaling processes in the developing and adult CNS. Furthermore, GSK-3 inhibition has been shown to have therapeutic effects in a wide array of neurological and neurodevelopmental disorders, including developmental alcohol toxicity. GSK-3 inhibition has been shown to exert therapeutic benefits in preclinical rodent models of stroke, Alzheimer's disease, bipolar disorder, and schizophrenia. The current proposal is based, in part, on published studies performed in collaboration with Dr. Allan's laboratory demonstrating that GSK-3 inhibition restores adult hippocampal neurogenesis and associated learning behaviors in a genetic mouse model of fragile x syndrome. Based on these findings, we hypothesize that GSK-3 inhibition also restores learning and neurogenic defects in our mouse model of moderate FASD. We will test this hypothesis using a combination of pharmacological and genetic approaches. Specifically, we propose to determine whether GSK-3P expression patterns are altered in adult hippocampus of FASD mice (Specific Aim 1), whether pharmacological inhibition of GSK-3 activity restores neurogenesis and improves functional plasticity of newborn granule neurons (Specific Aim 2) and whether inducible and selective gene deletion of GSK-3P in adult hippocampal progenitors improves neurogenesis and learning (Specific Aim 3). If successful, these studies will broaden our understanding of both FASD and GSK-3 mechanisms in adult neurogenesis, and could lead to identification of a novel therapeutic target for improving hippocampal function and reversing behavioral deficits in clinical FASD.

研究部分 3 将研究糖原合成酶激酶 3 (GSK-3) 作为 FASD 的潜在治疗靶点。该提案中概述的研究将测试以下假设：抑制 GSK-3 活性可逆转中度胎儿酒精谱系障碍 (FASD) 小鼠模型中成年海马神经发生和相关学习行为的缺陷。尽管 GSK-3 最初被发现是一种关键的代谢调节剂，但由于其能够调节发育中和成人 CNS 中的多种信号传导过程，因此研究兴趣重新兴起。此外，GSK-3 抑制已被证明对多种神经系统和神经发育障碍（包括发育性酒精毒性）具有治疗作用。 GSK-3 抑制已被证明可以在中风、阿尔茨海默病、双相情感障碍和精神分裂症的临床前啮齿动物模型中发挥治疗作用。目前的提议部分基于与 Allan 博士实验室合作进行的已发表研究，该研究表明 GSK-3 抑制可恢复脆性 X 综合征遗传小鼠模型中的成年海马神经发生和相关学习行为。基于这些发现，我们假设 GSK-3 抑制也能恢复中度 FASD 小鼠模型的学习和神经源性缺陷。我们将结合药理学和遗传学方法来检验这一假设。具体来说，我们建议确定 FASD 小鼠成年海马中 GSK-3P 表达模式是否发生改变（具体目标 1），GSK-3 活性的药物抑制是否可以恢复神经发生并改善新生颗粒神经元的功能可塑性（具体目标 2）以及成人海马祖细胞中 GSK-3P 的诱导性和选择性基因删除是否会改善神经发生和学习（具体目标 3）。如果成功，这些研究将拓宽我们对成人神经发生中 FASD 和 GSK-3 机制的理解，并可能导致确定一种新的治疗靶点，用于改善海马功能和逆转临床 FASD 的行为缺陷。