Cell Cycle Regulation in Fetal Alcohol Spectrum Disorders

胎儿酒精谱系疾病的细胞周期调节

基本信息

批准号：
10196890
负责人：
Karen Elizabeth Boschen
金额：
$ 11.96万
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：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10196890
关键词：
Address Affect Alcohols Apoptotic Cell Cycle Cell Cycle Arrest Cell Cycle Kinetics Cell Cycle Progression Cell Cycle Regulation Cell Cycle Stage Cell Differentiation process Cell Proliferation Cell Separation Cells ChIP-seq Chromatin Cilia Congenital Abnormality Corpus striatum structure Craniofacial Abnormalities DNA DNA Damage DNA Double Strand Break DNA Markers DNA Repair DNA biosynthesis Data Development Differentiation Antigens Dose Down-Regulation Embryo Enzymes Epigenetic Process Exposure to Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Flow Cytometry G1/S Transition Gene Expression Regulation Genes Goals Growth Histones Hour Human Image Impaired cognition Impairment Life Live Birth Modification Molecular Mus Neural Tube Closure Neural tube Normal Cell Pathogenicity Pathway interactions Pituitary Gland Ploidies Population Pregnancy Process Prosencephalon Proteins Replication Error Sampling Signal Transduction Site Sonic Hedgehog Pathway Structure Sumoylation Pathway Symptoms Techniques Testing Tissues Transforming Growth Factor beta Translations Ubiquitin Work alcohol exposure behavioral impairment brain abnormalities cdc Genes cell determination chromatin modification epigenetic regulation epigenome experimental study genome-wide human disease innovation insight mouse model novel novel strategies organ growth premature prenatal protein degradation protein expression protein protein interaction protein transport response therapeutic target therapy development transcriptome transcriptome sequencing

项目摘要

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.

项目摘要胎儿酒精谱系（FASD）每年最多影响美国5％的活产，并导致生命 - 长期的身体，认知和行为障碍。神经期间的酒精暴露，形成和神经管的关闭（人类怀孕的第四周，小鼠的妊娠日为8-10）是相关的中线结构异常生长，例如皮层，隔膜，垂体和心室，以及神经功能在以后的生活中发生变化。我的初步工作表明神经性阶段酒精会导致细胞周期停滞或延迟的细胞周期进展，导致增殖破坏，最终导致异常组织和器官发育。具体而言，我们进行了Rostroventral的整个转录组分析酒精暴露后的神经管6小时，发现许多基因和基因网络与细胞周期有关调节和细胞增殖通过酒精改变。此外，神经阶段的酒精引起声音刺猬（SHH）途径和细胞周期基因的明显失调。这些变化形态学信号传导与较小的鼻神经管相伴随酒精暴露的胚胎中的细胞。在此提案中，我们使用良好的FASD鼠标模型进行测试神经饮酒暴露的假设改变了鼻神经管中的细胞周期调节通过破坏调节细胞周期进程的过程。 AIM 1分析细胞周期停滞和G1- 产前酒精后神经管中的特定过程。初步数据表明失调控制细胞周期阶段和DNA损伤之间成功过渡的分子机制响应，可能导致DNA完整性和复制误差受损。 AIM 2调查了途径控制蛋白质降解和在细胞周期期间的运输，跟进先前的工作通过产前酒精编码泛素化酶的基因下调。最后，AIM 3检查与调节细胞周期进程的染色质相关的表观遗传标记，作为与在我们的初步研究中，发现染色质修饰会因神经阶段的饮酒而改变。这些实验将提供证据，表明细胞周期进程的机制代表了研究不足的产前酒精会导致FASD症状的途径。