Fetal Alcohol Exposure and Neurodevelopment

胎儿酒精暴露与神经发育

• 批准号: 7669338
• 负责人: Rajesh C Miranda
• 金额: $ 29.16万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7669338
• 关键词: Address; Adult; Alcohols; Automobile Driving; Biological; Biological Assay; Biological Process; Birth; Blast Cell; Brain; Categories; Cell Maturation; Cell Proliferation; Cell surface; Cells; Cerebrum; Child; Complex; Congenital Abnormality; Coupled; Data; Development; Disease; Dose; Environment; Epigenetic Process; Ethanol; Exhibits; Exposure to; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Flow Cytometry; Foundations; Functional RNA; Gene Expression Profile; Genes; Goals; Growth; Heterogeneity; In Vitro; Individual; Lead; Measures; Mediating; MicroRNAs; Microarray Analysis; Microcephaly; Modeling; Neuroepithelial; Neuroepithelial Cells; Neurons; Nuclear Pore Complex; Outcome; Pattern; Perinatal Exposure; Population; Positioning Attribute; Research; Resources; Rest; Reverse Transcriptase Polymerase Chain Reaction; Role; Second Pregnancy Trimester; Shapes; Staging; Stem cells; Supplementation; Technology; Teratogens; Testing; Therapeutic; Therapeutic Agents; Third Pregnancy Trimester; Ventricular; Withdrawal; Work; alcohol consumption during pregnancy; alcohol effect; alcohol exposure; alcohol sensitivity; base; brain malformation; cohort; combinatorial; developmental disease; experience; fetal; gliogenesis; in utero; in vivo; innovation; killings; mRNA Expression; mouse model; nerve stem cell; neurodevelopment; neuroepithelium; neurotoxic; novel; premature; prevent; progenitor; relating to nervous system; research study; stem; technology development

DESCRIPTION (provided by applicant): Alcohol is an important teratogen. Much research has focused on the sensitivity of the third- trimester period of brain development, where ethanol has been shown to be neuro-toxic. However, we know very little about the vulnerability of the second trimester period. The second trimester is important, because during this trimester, fetal neural stem (NSCs) and progenitor (NPCs) cells give rise to most neurons of the adult brain. Previously, we showed that ethanol did not kill fetal cortical NSCs/NPCs. Rather, ethanol induced cell proliferation, but depleted NSCs and NPCs, suggesting that ethanol promoted aberrant NSC maturation. Importantly, ethanol suppressed four microRNAs; small non-coding RNA molecules that control large gene networks to determine cell fate. Our central hypothesis is that ethanol depletes NSCs by driving stem to blast maturation of NSCs. A secondary hypothesis is that microRNAs mediate teratogenic effects of ethanol. We will address three specific aims. (Aim#l) To determine the extent to which ethanol promotes premature cortical neuroepithelial maturation. Our hypotheses are that (a) in utero binge ethanol exposure, during the second trimester period will significantly deplete resident NSCsINPCs and (b) isolated NSCs/NPCs will exhibit aberrant maturation patterns following ethanol exposure. We will test the ethanol- sensitivity of NSC/NPC populations using flow cytometric approaches. (Aim#2) To identify ethanol- sensitive microRNAs and their biological mechanisms. Our hypothesis is that ethanol persistently suppresses microRNAs that promote NSC/NPC renewal. We will use microarray technologies to identify candidate microRNAs, and manipulate levels of these microRNAs, to identify their role in NSC/NPC maturation. (Aim#3) To determine the extent to which ethanol-sensitive microRNAs prevent or reverse the effects of ethanol on fetal NSCs/NPCs. Our hypothesis is that microRNA supplementation will prevent and reverse ethanol's effects on NSC/NPC renewal and maturation. Cell biological approaches and mRNA expression analyses and will be used to assess the capacity of ethanol-regulated microRNAs to reverse or prevent the effects of prior ethanol exposure. At the end of the project period, we expect to have identified sensitive NSC/NPC populations, critical second-trimester periods of vulnerability to ethanol, and specific microRNAs and microRNA- mediated mechanisms that are persistently altered by ethanol. These outcomes will be significant because they are expected to provide the foundations for developing therapeutic strategies to manage the persistent neural effects of a leading teratogen. PUBLIC HELTH RELEVANCE Alcohol is a potent teratogen. Alcohol consumption during pregnancy can lead to a stereotypic spectrum of disorders in children, called the `Fetal Alcohol Spectrum Disorders' or FASD. At the neuroanatomical level, birth defects can include microencephaly and brain malformations. Much research has focused on the sensitivity of the third-trimester period of brain development, where ethanol has been shown to be neurotoxic. However, we know very little about the vulnerability of the second trimester period. The second trimester is important, because during this trimester, neuroepithelial cells of the ventricular walls give birth to millions of new neurons, creating a cellular framework for the rest of neural development. Previously, we showed that fetal cerebral cortical neuroepithelial cells did not die when exposed to ethanol. Rather, ethanol induced cell proliferation, while depleting cells expressing neural stem (NSC) and progenitor cell (NPC) markers. This proposal will test two hypotheses, that ethanol depletes stem and progenitor cells by driving stem to blast maturation of NSCs, and that the effects of ethanol are mediated by, and consequently, can be reversed by microRNAs. At the end of the project period, we expect to have identified sensitive NSC/NPC populations, critical second-trimester periods of vulnerability to ethanol, and specific microRNAs and microRNA-mediated mechanisms that are persistently altered by ethanol. These outcomes will be significant because they are expected to provide the foundations for developing therapeutic strategies to manage the persistent neural effects of a leading teratogen.

描述（由申请人提供）：酒精是重要的破坏力。许多研究集中在三个月发育的敏感性上，乙醇被证明是神经毒性的。但是，我们对第二孕期的脆弱性知之甚少。妊娠中期很重要，因为在此孕期，胎儿神经茎（NSC）和祖细胞（NPC）细胞会引起大多数成人大脑的神经元。以前，我们表明乙醇未杀死胎儿皮质NSC/NPC。相反，乙醇诱导细胞增殖，但耗尽了NSC和NPC，这表明乙醇促进了异常的NSC成熟。重要的是，乙醇抑制了四个microRNA。控制大基因网络以确定细胞命运的小非编码RNA分子。我们的中心假设是，乙醇通过驱动茎以爆炸NSC的成熟来耗尽NSC。次要假设是microRNA介导乙醇的致畸作用。我们将解决三个具体目标。 （目标＃L）确定乙醇促进过早皮质神经上皮成熟程度的程度。我们的假设是（a）在子宫狂饮乙醇暴露中，在第二个学期将大大耗尽居民NSCSINPC，并且（b）乙醇暴露后孤立的NSC/NPC将表现出异常的成熟模式。我们将使用流式细胞仪方法测试NSC/NPC种群的乙醇敏感性。 （目标＃2）鉴定乙醇敏感的microRNA及其生物学机制。我们的假设是乙醇持续抑制促进NSC/NPC更新的microRNA。我们将使用微阵列技术来识别候选microRNA，并操纵这些microRNA的水平，以鉴定其在NSC/NPC成熟中的作用。 （目标＃3）确定对乙醇敏感的microRNA的预防或逆转乙醇对胎儿NSC/NPC的影响的程度。我们的假设是补充microRNA将预防和逆转乙醇对NSC/NPC更新和成熟的影响。细胞生物学方法和mRNA表达分析，并将用于评估乙醇调节的microRNA逆转或防止先前乙醇暴露的作用的能力。在项目期结束时，我们希望已经确定了敏感的NSC/NPC人群，对乙醇的脆弱性关键时期以及乙醇持续改变的特定microRNAS和MicroRNA介导的机制。这些结果将是重要的，因为它们有望为制定治疗策略提供基础，以管理领先的伤明素的持续神经效应。公共Helth相关性酒精是一种有效的破坏力。怀孕期间的饮酒可以导致儿童疾病的刻板印象，称为“胎儿酒精疾病”或FASD。在神经解剖学水平上，先天缺陷可以包括微脑和脑畸形。许多研究集中在大脑发育的第三孕期的敏感性上，乙醇被证明是神经毒性的。但是，我们对第二孕期的脆弱性知之甚少。妊娠中期很重要，因为在这个三个月中，心室壁的神经上皮细胞孕育了数百万个新的神经元，从而为其余的神经发育创造了细胞框架。以前，我们表明胎儿脑皮质神经上皮细胞在暴露于乙醇时不会死亡。相反，乙醇诱导细胞增殖，同时耗尽表达神经茎（NSC）和祖细胞（NPC）标记的细胞。该建议将检验两个假设，即通过驱动茎以爆炸NSC的成熟，乙醇耗竭茎和祖细胞，并且乙醇的作用是由microRNA介导的，因此可以通过microRNAS逆转。在项目期结束时，我们希望已经确定了敏感的NSC/NPC人群，对乙醇的脆弱性关键时期以及特定的microRNA和MicroRNA介导的机制，这些机制持续改变了乙醇。这些结果将是重要的，因为它们有望为制定治疗策略提供基础，以管理领先的伤明素的持续神经效应。