Sex-dependent effects of prenatal alcohol exposure on developmental programming

项目摘要 产前酒精暴露（PAE）与发育，认知，行为和身体有关。 胎儿酒精谱系障碍（FASD）患病率为2到5/100 儿童和估计增加的21,000美元的年度费用为个人患有FASD，治疗的目的是 治疗FASD将具有显著的社会效益。我们的目标是确定分子机制， 酒精会改变发育中的胎儿，并利用这些信息来推进有针对性的干预措施， 扭转或减少PAE的长期后果。 PAE“程序”的有机体的发展，产生的变化，可以持续整个生命周期。在 在许多情况下，PAE的作用是由糖皮质激素（GC）通过糖皮质激素受体介导的 (GRs)并且受到生物体性别的影响。我们假设PAE改变了子宫内 由于方案扩大教育对儿童的影响不同， 胎盘和胎儿大脑水平为1。11β-HSD 1和11β-HSD 2，催化活性和 非活性GC，和2.）长的非编码RNA生长抑制特异性5（Gas 5），其结合GR DNA- 结合域，抑制GR依赖性基因表达。这些研究将确定PAE对 microRNA介导的调节GR编程的机制。此外，我们评估了胎盘的作用， 外泌体作为PAE对胎儿脑Gas影响的介质5.阐明PAE对 胎盘11β-HSDs、Gas 5和外泌体可用于鉴定1）。用于识别酒精的生物标志物 在人类怀孕期间食用，2.）后代结果的预测因子，以及3.）新靶标在 治疗FASD。

PROJECT SUMMARY Prenatal alcohol exposure (PAE) is associated with developmental, cognitive, behavioral, and physical abnormalities termed Fetal Alcohol Spectrum Disorders (FASD). With a prevalence ranging from 2 to 5 in 100 children and an estimated added annual cost of $21,000 for an individual afflicted with FASD, therapies aimed at treating FASD will be of significant societal benefit. Our goal is to identify molecular mechanisms through which alcohol alters the developing fetus and to use this information to advance targeted interventions that reverse or reduce the long-term consequences of PAE. PAE “programs” development of the organism, producing changes that can persist throughout the lifespan. In many cases, the effects of PAE are mediated by glucocorticoids (GCs) acting via glucocorticoid receptors (GRs) and are influenced by the sex of the organism. We hypothesize that PAE modifies the in utero programming of GRs in a sex- and development-specific manner as the result of differential effects of PAE on placental and fetal brain levels of 1.) 11β-HSD1 and 11β-HSD2, which catalyze interconversion of active and inactive GC, and 2.) the long noncoding RNA Growth arrest-specific 5 (Gas5), which binds to the GR DNA- binding domain, inhibiting GR-dependent gene expression. These studies will identify effects of PAE on microRNA-mediated mechanisms that regulate GR programming. Additionally, we assess the role of placental exosomes as mediators of the effects of PAE on fetal brain Gas5. Elucidation of the effects of PAE on placental 11β-HSDs, Gas5 and exosomes may serve to identify 1.) biomarkers for identification of alcohol consumption during human pregnancy, 2.) predictors of progeny outcomes, and 3.) novel targets for the treatment of FASDs.