Characterizing the Genetics of FASD in Complementary Mouse and Fish Models

在互补小鼠和鱼类模型中描述 FASD 的遗传学特征

基本信息

  • 批准号:
    10792720
  • 负责人:
  • 金额:
    $ 56.69万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-15 至 2028-07-31
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract Alcohol (ethanol) exposure during pregnancy is the leading environmental cause of birth defects and central nervous system dysfunction. While the effects of ethanol on the brain and face have been explored quite extensively, there is considerable variation in the consequences of developmental ethanol exposure. Some of this variation is due to differences in timing and amount of exposure or nutritional factors. However, even when controlling for these factors, it is still clear that not everyone exposed to ethanol during development is affected equally and it has become increasingly clear that genetic factors play a very significant role in fetal alcohol spectrum disorders (FASD). Historically, elucidating these genetic factors that mediate risk or resilience has been relatively slow and characterized by human association studies or quantitative trait loci mapping in animal models. More recently, we have applied next generation sequencing technologies and forward genetic screens to more rapidly identify genes and pathways that alter susceptibility to prenatal ethanol exposure. These studies have taken advantage of varied mouse strains with differential alcohol susceptibility, numerous transgenic mouse lines, and high throughput zebrafish genetic analyses and CRISPR/Cas9 gene editing techniques. In this current proposal, we will further these approaches with the combination of the powerful genomic analyses capabilities of the Collaborative Cross mouse genetics tools. In Aim 1, we will explore mechanisms underlying ethanol sensitivity using complementary mouse and fish transgenic lines, while identifying further candidate genes via comparisons of the highly ethanol susceptible mouse strain, C57BL/6J vs. the highly ethanol resistant strain 129S1/Svlmj. This comparison will be aided by embryonic transcriptomic (RNA-Seq) analyses, selective crossbreeding to induce susceptibility in a resistant line (129) with extensive genome sequencing analyses. Aim 2 will significantly expand our genomic analyses by examining CC founder strains for their susceptibility to ethanol followed by transcriptomic profiling of susceptible and resistant strains. Conserved candidate genes and pathways will be further tested and characterized in our high throughput zebrafish phenotyping analyses. Aim 3 will take a complementary bioinformatic approach by identifying chemical modifiers of gene-ethanol interactions in a high throughput zebrafish screen with further confirmation in our mouse model of FASD. This proposal brings together experts on mouse and fish genetics, embryology and alcohol teratology. Together, these experiments will greatly enhance our understanding of the genetic etiology of ethanol-induced brain and craniofacial malformations during early embryonic development, as well as aiding in the identification of the pathogenic mechanisms involved in FASD.
项目摘要/摘要 孕期接触酒精是导致出生缺陷的主要环境原因, 神经系统功能障碍。虽然酒精对大脑和脸部的影响已经被很好地研究了 广泛地说,发育期酒精暴露的后果有相当大的差异。其中一些 这种差异是由于暴露或营养因素的时间和数量的不同。然而,即使当 控制这些因素,仍然清楚的是,并不是每个在发育过程中接触乙醇的人都会受到影响 同样,越来越清楚的是,遗传因素在胎儿酒精中起着非常重要的作用 谱系障碍(FASD)。从历史上看,阐明这些调节风险或韧性的遗传因素 相对缓慢,以人类联想研究或动物数量性状基因座定位为特征 模特们。最近,我们应用了下一代测序技术和前向基因筛查 以更快地确定改变产前酒精暴露易感性的基因和途径。这些 研究利用了具有不同酒精敏感性的不同小鼠品系,许多 转基因小鼠品系、高通量斑马鱼遗传分析和CRISPR/Cas9基因编辑 技巧。在目前的提案中,我们将通过将强大的 协作杂交小鼠遗传学工具的基因组分析能力。在目标1中,我们将探索 利用互补的小鼠和鱼类转基因系研究乙醇敏感性的机制,而 通过与乙醇高度敏感的小鼠品系C57BL/6J的比较进一步确定候选基因 与高乙醇抗性菌株129S1/Svlmj的比较。这种比较将得到胚胎转录学的帮助。 (RNA-Seq)分析,选择性杂交诱导抗性品系(129)具有广泛的 基因组测序分析。Aim 2将通过检查CC创始人来显著扩展我们的基因组分析 检测菌株对乙醇的敏感性,然后对敏感和耐药菌株进行转录图谱分析。 保守的候选基因和途径将在我们的高吞吐量下进行进一步的测试和表征 斑马鱼表型分析。目标3将采取补充生物信息学的方法,通过识别 高通量斑马鱼筛选中基因-乙醇相互作用的化学修饰物进一步证实 在我们的FASD小鼠模型中。这项建议汇集了老鼠和鱼类遗传学、胚胎学等方面的专家 和酒精畸形学。总之,这些实验将极大地增强我们对基因 酒精致胚胎发育早期脑部和颅面畸形的病因研究 有助于确定FASD的致病机制。

项目成果

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JOHANN K EBERHART其他文献

JOHANN K EBERHART的其他文献

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{{ truncateString('JOHANN K EBERHART', 18)}}的其他基金

Mechanisms underlying the multifaceted basis of craniofacial dysmorphogenesis
颅面畸形发生的多方面基础机制
  • 批准号:
    10645146
  • 财政年份:
    2019
  • 资助金额:
    $ 56.69万
  • 项目类别:
Mechanisms underlying the multifaceted basis of craniofacial dysmorphogenesis
颅面畸形发生的多方面基础机制
  • 批准号:
    10190896
  • 财政年份:
    2019
  • 资助金额:
    $ 56.69万
  • 项目类别:
Mechanisms underlying the multifaceted basis of craniofacial dysmorphogenesis
颅面畸形发生的多方面基础机制
  • 批准号:
    10426217
  • 财政年份:
    2019
  • 资助金额:
    $ 56.69万
  • 项目类别:
Genetic and epigenetic interactions underlying FASD
FASD 背后的遗传和表观遗传相互作用
  • 批准号:
    9196218
  • 财政年份:
    2016
  • 资助金额:
    $ 56.69万
  • 项目类别:
Causes of Variability in Craniofacial Disease
颅面疾病变异的原因
  • 批准号:
    8067161
  • 财政年份:
    2010
  • 资助金额:
    $ 56.69万
  • 项目类别:
Causes of Variability in Craniofacial Disease
颅面疾病变异的原因
  • 批准号:
    8656967
  • 财政年份:
    2010
  • 资助金额:
    $ 56.69万
  • 项目类别:
Causes of Variability in Craniofacial Disease
颅面疾病变异的原因
  • 批准号:
    8462125
  • 财政年份:
    2010
  • 资助金额:
    $ 56.69万
  • 项目类别:
Causes of Variability in Craniofacial Disease
颅面疾病变异的原因
  • 批准号:
    8268932
  • 财政年份:
    2010
  • 资助金额:
    $ 56.69万
  • 项目类别:
Genetic Hierarchies and Cellular Behaviors during Zebrafish Palatogenesis
斑马鱼腭发育过程中的遗传层次和细胞行为
  • 批准号:
    7841071
  • 财政年份:
    2009
  • 资助金额:
    $ 56.69万
  • 项目类别:
Genetic Hierarchies and Cellular Behaviors during Zebrafish Palatogenesis
斑马鱼腭发育过程中的遗传层次和细胞行为
  • 批准号:
    7324079
  • 财政年份:
    2006
  • 资助金额:
    $ 56.69万
  • 项目类别:

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