GSK-3 as a Therapeutic Target for 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。本提案中概述的研究将在中度胎儿酒精谱系障碍（FASD）小鼠模型中验证抑制GSK-3活性逆转成人海马神经发生和相关学习行为缺陷的假设。虽然最初发现GSK-3是一种关键的代谢调节因子，但由于其调节发育和成人中枢神经系统的多种信号过程的能力，GSK-3的研究兴趣重新燃起。此外，GSK-3抑制已被证明对多种神经和神经发育障碍具有治疗作用，包括发育性酒精毒性。GSK-3抑制已在中风、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显示出治疗益处。目前的建议部分基于与Allan博士实验室合作进行的已发表的研究，这些研究表明GSK-3抑制可以恢复脆性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抑制也可以恢复中度FASD小鼠模型的学习和神经源性缺陷。我们将使用药理学和遗传学方法的结合来检验这一假设。具体而言，我们拟确定FASD小鼠成年海马中GSK-3P表达模式是否发生改变（Specific Aim 1），药理抑制GSK-3活性是否恢复神经发生并改善新生颗粒神经元的功能可塑性（Specific Aim 2），以及成年海马祖细胞中诱导和选择性删除GSK-3P基因是否改善神经发生和学习（Specific Aim 3）。如果成功，这些研究将拓宽我们对FASD和GSK-3在成人神经发生中的机制的理解，并可能导致发现改善海马功能和逆转临床FASD行为缺陷的新治疗靶点。

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.