Ovine Model System for Alcohol Related Birth Defects

超出提供的空间。|我们现在已经建立了一个研究TAS的绵羊模型系统的可行性，并将在这次续订申请中利用该系统提供的独特优势。胎儿酒精暴露(BACs为260 mg/dl)可引起脑细胞丢失，但不会导致胎儿低氧血症。然而，酒精仍然有可能通过改变血液流动来减少氧气向大脑的输送。具体目标#1将通过将同位素标记的微球融合到长期使用仪器的胎羊的循环中来测量酒精敏感脑区的血液低水平，来测试以下假设：胎儿酒精暴露减少了局部脑血流量，从而在不降低血氧含量的情况下减少了氧气的输送。此外，酒精暴露可导致母体低氧血症和酸血症以及无胎儿低氧血症的其他酸血症。具体目标#2将测试这样一个假设，即反复发作的中度酸血症通过操纵母亲吸入的气体浓度来产生与酒精暴露类似的母体和全身血气，并将其与酒精敏感脑区的神经元数量联系起来，从而介导胎儿脑损伤。我们发现酒精作用于胎盘两侧，刺激下丘脑、垂体、肾上腺轴。具体目标#3将检验酒精暴露引起的胎儿皮质醇升高在调节胎儿脑损伤中的作用这一假设。最后，尽管Fas在近30年前就被发现了，但还没有研究探索将大量饮酒限制在怀孕早期的好处。具体目标#4测试假设，将酒精暴露限制在怀孕前三个月将导致脑损伤，但在数量和质量上不同于所有三个月期间的暴露或限制到第三个月的暴露(前一资助期调查的期间)造成的损伤。综上所述，我们推测，如果酒精通过酸血症、缺氧或胎儿皮质醇增加而间接诱导细胞损失，那么通过操纵这些变量到与酒精相似但独立于酒精给药的程度来获得细胞OS将从机械上测试它们在介导脑损伤中的作用。总而言之，这些假设驱动的研究只在绵羊等动物模型系统中实用，将回答损害的重要机制、时间和区域脆弱性问题，并将提供独特的数据，这些数据可能对说服孕妇在怀孕早期停止或减少饮酒非常重要。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. |we now have established the feasibility or a sheep model system to investigate t AS and will exploit the unique .dvantages offered by this system in this renewal application. Fetal alcohol exposure (BACs of 260 mg/dl) iroduced brain cell loss but did not result in fetal hypoxemia. However, it is still possible that alcohol reduces ixygen delivery to the brain by altering blood flow. Specific aim #1 will test the hypothesis that fetal alcohol xposure decreases local brain blood flow and thus oxygen delivery without decreasing blood oxygen content by nfusing isotope-labeled microspheres into the circulation of chronicallyinstrumented fetal sheep to measure blood low in alcohol-sensitive brain regions. Also, alcohol exposure resulted in maternal hypoxemia and acidemia and etal acidemia without fetal hypoxemia. Specific aim #2 will test the hypothesis that repeated episodes of moderate acidemia mediate fetal brain injury by manipulating the maternal inspired gas concentrations to create maternal and etal blood gases like those mediated by alcohol exposure and relate this to neuron numbers in alcohol-sensitive brain regions. We found that alcohol acts on both sides of the placenta to stimulate.the hypothalamus pituitary adrenal axes. Specific aim #3 will test the hypothesis that elevations of fetal cortisol as a result of alcohol exposure >lay a role in mediating fetal brain injury. And finally, although FAS was identified almost 30 years ago, no studies lave yet explored the advantages to the conceptus of limiting heavy drinking to the first trimester. Specific aim #4 test the hypothesis that alcohol exposure limited to the first trimester will result in brain injury, but injury that differs quantitatively and qualitatively from that resulting from exposure during all three trimesters or exposure imited to the third trimester (the periods investigated during the previous funding period). In summary, we reason hat if alcohol induces cell loss indirectly, via acidemia, hypoxia or increases in fetal cortisol, then obtaining cell oss by manipulating these variables to a degree similar to that achieved by alcohol but independent of alcohol administration will mechanistically test.their roles in mediating brain injury. Together, these hypothesis-drive; studies that are practical only in an animal model system such as the sheep will answer important mechanism o damage, temporal and regional vulnerability questions and also will provide unique data that could be ve mportant in helping to persuade pregnant women to stop or reduce their drinking early in pregnancy. PERFORMANCE SITE ========================================Section End===========================================