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：
10873539
负责人：
Karen Elizabeth Boschen
金额：
$ 24.82万
依托单位：
UPSTATE MEDICAL UNIVERSITY
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 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10873539
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 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 Post-Translational Protein Processing Pregnancy Process Proliferating Prosencephalon Protein Dynamics Proteins Replication Error Sampling Signal Transduction Site Sonic Hedgehog Pathway Structure Sumoylation Pathway Symptoms Techniques Testing Tissues Transforming Growth Factor beta Ubiquitin Visualization Work alcohol exposure behavioral impairment brain abnormalities cdc Genes cell determination cell preparation chromatin modification embryonic alcohol exposure epigenetic regulation epigenome experimental study gene network gene repression 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 sequencing transcriptomic profiling

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.

项目概要胎儿酒精谱系障碍 (FASD) 每年影响美国高达 5% 的活产婴儿，并导致生命- 长期的身体、认知和行为障碍。神经形成过程中的酒精暴露、形成和神经管的闭合（人类妊娠第 4 周，小鼠妊娠第 8-10 天），与中线结构异常生长，如皮质、隔膜、垂体和心室，以及晚年的神经功能变化。我的初步工作表明神经形成阶段的酒精会导致细胞周期停滞或细胞周期进展延迟，导致增殖破坏，最终导致异常组织和器官发育。具体来说，我们对 rostroventral 进行了全转录组分析酒精暴露6小时后的神经管，发现许多与细胞周期相关的基因和基因网络酒精改变了调节和细胞增殖。此外，神经发育阶段的酒精也会导致音刺猬 (Shh) 通路和细胞周期基因的显着失调。这些变化形态发生信号伴随着较小的头侧神经管体积和较少的活跃分裂暴露于酒精的胚胎中的细胞。在本提案中，我们使用特征良好的 FASD 小鼠模型来测试神经形成阶段酒精暴露改变头侧神经管细胞周期调节的假设通过破坏调节细胞周期进程的过程。目标 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反应，可能导致 DNA 完整性受损和复制错误。目标 2 研究途径继之前的研究之后，控制细胞周期中的蛋白质降解和运输产前酒精下调编码泛素化酶的基因。最后，目标 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，发现神经形成阶段的酒精会改变染色质修饰。这些实验将提供证据表明细胞周期进展的机制尚未得到充分研究产前酒精导致 FASD 症状的途径。