Cell Cycle Regulation in Fetal Alcohol Spectrum Disorders

项目摘要 胎儿酒精谱系障碍（FASD）每年影响美国多达5%的活产婴儿，并导致生命- 长期的身体、认知和行为障碍。神经胚形成过程中的酒精暴露， 神经管闭合（人类妊娠约4周，小鼠妊娠8 - 10天）与 中线结构异常生长，如皮质、隔膜、垂体和脑室，以及 神经功能的变化。我的初步研究表明，神经发育阶段的酒精会导致细胞 周期停滞或延迟细胞周期进程，导致增殖中断，最终导致异常 组织和器官发育。具体地说，我们进行了整个转录组分析的吻腹侧 结果发现，酒精暴露后6小时，神经管中有许多与细胞周期相关的基因和基因网络 调节和细胞增殖被酒精改变。此外，神经发育阶段的酒精导致 Sonic Hedgehog（Shh）通路和细胞周期基因的显著失调。的这些变化 形态发生信号伴随着更小的吻侧神经管体积和更少的活跃分裂 酒精暴露的胚胎中的细胞。在这个建议中，我们使用一个良好表征的FASD小鼠模型来测试 神经形成期酒精暴露改变吻侧神经管细胞周期调节的假说 通过破坏调节细胞周期进程的过程。目的1分析细胞周期阻滞和G1- 产前饮酒后神经管中的特定过程。初步数据表明， 控制细胞周期阶段和DNA损伤之间成功过渡的分子机制 反应，可能导致DNA完整性受损和复制错误。目标2研究的途径， 控制蛋白质的降解和运输在细胞周期中，后续工作显示， 产前酒精下调编码泛素化酶的基因。最后，目标3检查 与染色质相关的调节细胞周期进程的表观遗传标记，如与 在我们的初步研究中，发现神经形成阶段的酒精改变了染色质修饰。这些 实验将提供证据表明，细胞周期进程的机制代表了一个研究不足的 产前酒精导致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.