Fetal Alcohol Exposure and Neurodevelopment
胎儿酒精暴露与神经发育
基本信息
- 批准号:7669338
- 负责人:
- 金额:$ 29.16万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAdultAlcoholsAutomobile DrivingBiologicalBiological AssayBiological ProcessBirthBlast CellBrainCategoriesCell MaturationCell ProliferationCell surfaceCellsCerebrumChildComplexCongenital AbnormalityCoupledDataDevelopmentDiseaseDoseEnvironmentEpigenetic ProcessEthanolExhibitsExposure toFetal Alcohol ExposureFetal Alcohol Spectrum DisorderFlow CytometryFoundationsFunctional RNAGene Expression ProfileGenesGoalsGrowthHeterogeneityIn VitroIndividualLeadMeasuresMediatingMicroRNAsMicroarray AnalysisMicrocephalyModelingNeuroepithelialNeuroepithelial CellsNeuronsNuclear Pore ComplexOutcomePatternPerinatal ExposurePopulationPositioning AttributeResearchResourcesRestReverse Transcriptase Polymerase Chain ReactionRoleSecond Pregnancy TrimesterShapesStagingStem cellsSupplementationTechnologyTeratogensTestingTherapeuticTherapeutic AgentsThird Pregnancy TrimesterVentricularWithdrawalWorkalcohol consumption during pregnancyalcohol effectalcohol exposurealcohol sensitivitybasebrain malformationcohortcombinatorialdevelopmental diseaseexperiencefetalgliogenesisin uteroin vivoinnovationkillingsmRNA Expressionmouse modelnerve stem cellneurodevelopmentneuroepitheliumneurotoxicnovelprematurepreventprogenitorrelating to nervous systemresearch studystemtechnology development
项目摘要
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(申请人提供):酒精是一种重要的致畸物质。许多研究都集中在大脑发育后期的敏感性上,在这一时期,乙醇被证明是神经毒性的。然而,我们对怀孕中期的脆弱性知之甚少。第二个三个月很重要,因为在这个三个月期间,胎儿神经干细胞(NSCs)和祖细胞(NPC)形成了成年大脑的大部分神经元。此前,我们发现乙醇不会杀死胎儿皮质神经干细胞/神经前体细胞。相反,乙醇促进了细胞的增殖,但耗尽了神经干细胞和神经干细胞,这表明乙醇促进了神经干细胞的异常成熟。重要的是,乙醇抑制了四个microRNAs,即控制大型基因网络以决定细胞命运的非编码小RNA分子。我们的中心假设是乙醇通过驱动NSCs的茎向原始成熟来耗尽NSCs。第二个假设是,microRNAs介导了乙醇的致畸效应。我们将解决三个具体目标。(目的#L)确定乙醇在多大程度上促进皮质神经上皮细胞的早熟。我们的假设是:(A)宫内过度酒精暴露,在妊娠中期将显著消耗常驻的NSCs-INPC;(B)在乙醇暴露后,分离的NSCs/NPC将表现出异常的成熟模式。我们将使用流式细胞术检测NSC/NPC群体对酒精的敏感性。(目的#2)鉴定乙醇敏感的microRNAs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microRNAs。我们将使用微阵列技术来识别候选的microRNAs,并操纵这些microRNAs的水平,以确定它们在NSC/NPC成熟中的作用。(目的#3)确定乙醇敏感的microRNA在多大程度上阻止或逆转乙醇对胎儿NSCs/NPC的影响。我们的假设是,补充microRNA将阻止和逆转乙醇对NSC/NPC更新和成熟的影响。细胞生物学方法和mRNA表达分析,并将用于评估酒精调节的microRNAs逆转或防止先前酒精暴露的影响的能力。在项目期结束时,我们预计已经确定了敏感的NSC/NPC群体、对乙醇脆弱的关键中期阶段,以及特定的microRNAs和microRNA介导的机制,这些机制一直被乙醇改变。这些结果将是重要的,因为它们有望为开发治疗策略提供基础,以管理领先致畸剂的持续神经影响。公共卫生相关酒精是一种潜在的致畸物质。怀孕期间饮酒会导致儿童的一种刻板印象的疾病谱系,称为“胎儿酒精谱系障碍”或FASD。在神经解剖学层面上,出生缺陷可能包括小脑畸形和脑畸形。许多研究都集中在大脑发育的第三个月阶段的敏感性上,在这个阶段,乙醇被证明是神经毒性的。然而,我们对怀孕中期的脆弱性知之甚少。第二个三个月很重要,因为在这个三个月期间,脑室壁的神经上皮细胞会产生数以百万计的新神经元,为其余的神经发育创造一个细胞框架。此前,我们发现胎儿大脑皮质神经上皮细胞在接触乙醇时不会死亡。相反,乙醇诱导细胞增殖,同时耗尽表达神经干细胞(NSC)和祖细胞(NPC)标记的细胞。这项提议将检验两个假设,即乙醇通过驱动神经干细胞的干到母细胞成熟来耗尽干细胞和祖细胞,以及乙醇的影响是由microRNAs介导的,因此可以被microRNAs逆转。在项目期结束时,我们预计已经确定了敏感的NSC/NPC群体、对乙醇脆弱的关键中期阶段,以及特定的microRNAs和microRNA介导的机制,这些机制一直被乙醇改变。这些结果将是重要的,因为它们有望为开发治疗策略提供基础,以管理领先致畸剂的持续神经影响。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Rajesh C Miranda其他文献
Rajesh C Miranda的其他文献
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{{ truncateString('Rajesh C Miranda', 18)}}的其他基金
Impact of Prenatal alcohol on Alzheimer's disease related pathology and cognitive impairment
产前酒精对阿尔茨海默病相关病理和认知障碍的影响
- 批准号:
10387300 - 财政年份:2022
- 资助金额:
$ 29.16万 - 项目类别:
Impact of Prenatal alcohol on Alzheimer's disease related pathology and cognitive impairment
产前酒精对阿尔茨海默病相关病理和认知障碍的影响
- 批准号:
10570173 - 财政年份:2022
- 资助金额:
$ 29.16万 - 项目类别:
Prenatal alcohol and stroke susceptibility in the aging adult with FASD
患有 FASD 的老年人的产前酒精和中风易感性
- 批准号:
10396634 - 财政年份:2018
- 资助金额:
$ 29.16万 - 项目类别:
Prenatal alcohol and stroke susceptibility in the aging adult with FASD
患有 FASD 的老年人的产前酒精和中风易感性
- 批准号:
9915821 - 财政年份:2018
- 资助金额:
$ 29.16万 - 项目类别:
Prenatal alcohol and stroke susceptibility in the aging adult with FASD
患有 FASD 的老年人的产前酒精和中风易感性
- 批准号:
10172800 - 财政年份:2018
- 资助金额:
$ 29.16万 - 项目类别:
Prenatal microRNA neuro-therapeutics for fetal alcohol exposure
针对胎儿酒精暴露的产前 microRNA 神经疗法
- 批准号:
9240564 - 财政年份:2016
- 资助金额:
$ 29.16万 - 项目类别:
Prenatal microRNA neuro-therapeutics for fetal alcohol exposure
针对胎儿酒精暴露的产前 microRNA 神经疗法
- 批准号:
9044875 - 财政年份:2016
- 资助金额:
$ 29.16万 - 项目类别:
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