Ovine Model System for Alcohol Related Birth Defects

超出所提供的空间。|我们现在已经建立了一个可行的绵羊模型系统来研究AS，并将在这一更新应用中利用该系统所提供的独特优势。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输送到大脑。具体目标#1将通过将同位素标记的微球注入长期仪器化的胎羊循环中以测量酒精敏感脑区域的血液浓度来检验胎儿酒精暴露降低局部脑血流量并因此降低氧输送而不降低血氧含量的假设。此外，酒精暴露导致母亲低氧血症和酸血症，而胎儿没有低氧血症。具体目标#2将检验以下假设：中度酸血症的反复发作通过操纵母体吸入气体浓度来产生类似于酒精暴露介导的母体和埃塔尔血气，并将其与酒精敏感脑区的神经元数量相关联，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将检验酒精暴露导致胎儿皮质醇升高在介导胎儿脑损伤中发挥作用的假设。最后，尽管FAS在近30年前就被发现了，但还没有研究探讨过将大量饮酒限制在怀孕的头三个月对胎儿的好处。具体目标#4检验以下假设：仅限于前三个月的酒精暴露将导致脑损伤，但损伤在数量和质量上不同于所有三个月的暴露或仅限于后三个月的暴露（前一个资助期内调查的时期）。总之，我们推断，如果酒精通过酸血症、缺氧或胎儿皮质醇增加间接诱导细胞损失，那么通过操纵这些变量获得细胞损失，达到与酒精相似的程度，但独立于酒精给药，将机械地测试它们在介导脑损伤中的作用。总之，这些假设驱动的研究仅在动物模型系统（如绵羊）中实用，将回答重要的损伤机制，时间和区域脆弱性问题，并提供独特的数据，有助于说服孕妇在怀孕早期停止或减少饮酒。性能现场=

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===========================================