Cell Cycle Regulation in Fetal Alcohol Spectrum Disorders

项目摘要 在美国，胎儿酒精谱系障碍(FASD)每年影响高达5%的活产儿，并导致生命- 长期的身体、认知和行为障碍。在神经形成过程中酒精暴露，形成和 神经管的关闭(人类怀孕4周，小鼠怀孕8-10天)与 中线结构异常生长，如皮质、隔膜、垂体和脑室，以及 在以后的生活中神经功能的变化。我的初步工作表明，神经形成期的酒精会导致细胞 细胞周期停滞或延缓细胞周期进程，导致细胞增殖中断，并最终出现异常 组织和器官发育。具体地说，我们对轮状腹侧进行了完整的转录组分析。 神经管在酒精暴露6小时后发现，许多基因和基因网络与细胞周期有关 酒精改变了细胞的调节和细胞增殖。此外，神经形成期酒精还会导致 Sonic Hedgehog(Shh)途径和细胞周期基因的显著失调。这些变化在 形态发生信号伴随着较小的吻端神经管体积和较少的活跃分裂 酒精暴露的胚胎中的细胞。在这个方案中，我们使用一个特征良好的FASD小鼠模型来测试 神经形成期酒精暴露改变嘴神经管细胞周期调节的假说 通过扰乱调节细胞周期进程的过程。AIM 1分析细胞周期停滞和G1- 产前饮酒后神经管中的特定过程。初步数据显示， 控制细胞周期阶段与DNA损伤之间成功转换的分子机制 响应，可能导致DNA完整性受损和复制错误。AIM 2研究的是 在细胞周期中控制蛋白质的降解和运输，跟进之前的工作显示 产前酒精对泛素化酶编码基因的下调作用。最后，Aim 3考查 与染色质相关的、调节细胞周期进程的表观遗传标记，作为与 在我们的初步研究中，发现神经形成期的酒精改变了染色质的修饰。这些 实验将提供证据，证明细胞周期进程的机制是一个研究不足的 产前酒精引起FASD症状的途径。

Project Summary Fetal Alcohol Spectrum Disorders (FASD) affects up to 5% of live births in the US each year and results in life- long physical, cognitive, and behavioral impairments. Alcohol exposure during neurulation, the formation and closure of the neural tube (~ 4th week of pregnancy in humans, gestational days 8-10 in mice), is associated with abnormal growth of midline structures, such as the cortex, septum, pituitary, and ventricles, and neurofunctional changes later in life. My preliminary work suggested that neurulation-stage alcohol causes cell cycle arrest or delayed cell cycle progression, resulting in disrupted proliferation and, ultimately, anomalous tissue and organ development. Specifically, we performed whole transcriptome profiling of the rostroventral neural tube 6 hr after alcohol exposure and found that many genes and gene networks related to cell cycle regulation and cell proliferation were altered by alcohol. In addition, neurulation-stage alcohol caused significant dysregulation of the sonic hedgehog (Shh) pathway and cell cycle genes. These changes in morphogenic signaling were concomitant with smaller rostral neural tube volumes and fewer actively dividing cells in alcohol-exposed embryos. In this proposal, we use a well-characterized mouse model of FASD to test the hypothesis that neurulation-stage alcohol exposure alters cell cycle regulation in the rostral neural tube through disruption of processes that regulate cell cycle progression. Aim 1 analyzes cell cycle arrest and G1- specific processes in the neural tube following prenatal alcohol. Preliminary data suggest dysregulation of molecular mechanisms that control the successful transition between cell cycle stages and the DNA damage response, possibly leading to impaired DNA integrity and replication errors. Aim 2 investigates pathways that control protein degradation and trafficking during the cell cycle, following up on previous work showing downregulation of genes encoding ubiquitylation enzymes by prenatal alcohol. Finally, Aim 3 examines epigenetic marks associated with chromatin that regulate cell cycle progression, as pathways related to chromatin modifications were found to altered by neurulation-stage alcohol in our preliminary studies. These experiments will provide evidence that mechanisms of cell cycle progression represent an under-studied pathway through which prenatal alcohol causes symptoms of FASD.