Brain Circulatory Adaptations of Fetal Alcohol Spectrum Disorders

产前酒精暴露（PAE）可对发育中的胎儿造成一系列不可逆的损害， 胎儿酒精谱系障碍（FASD）酒精在怀孕期间的作用是复杂的， 无数的异质性结果，几乎可以影响每个胎儿器官系统。迄今为止， FASD有治疗药物，估计美国学龄儿童的患病率为3-9% 尽管几乎每个大脑区域都表现出对PAE的脆弱性，但仍然存在大量的知识差距 关于PAE如何影响发育中大脑的血管功能。流通基础设施发展 伴随着大脑，因此，脑循环功能的损害可能导致营养物质的改变， 氧气、代谢物和激素在关键发育窗口期间输送到大脑。交付这些 底物是必要的适当的神经发育，因此，酒精引起的干扰， 底物递送到大脑可能对神经发育结果具有深远的影响。 在我们建立的FASD大鼠模型中，我们利用高频超声产生了初步数据 在子宫内，表明慢性重度PAE损害大脑中动脉血流和速度时间间隔， 这是一个被广泛使用的抗药性指标。初步数据进一步表明，PAE导致受损的中间 脑动脉（MCA）激动剂诱导的剂量依赖性血管舒张。在目标1中，我们将测试PAE是否会改变胎儿 在我们的FASD模型中的颅向血流。为了实现这一目标，我们将利用非侵入性，超高 高频超声检查，以获得彩色和脉搏波多普勒测量胎儿心率，心脏 输出量、血流量和直接供血的主要动脉网络中的血管阻力指数 大脑（主动脉、颈内动脉和MCA）。目标2将测试PAE是否会损害对灌注的反应 脑血管压力在早期发展。为了实现这一目标，我们将在MCA插管， 阻力动脉，直接供应大脑，并将评估PAE是否改变适应压力依赖性 血管反应目标3将测试PAE是否通过内皮细胞损伤诱导脑动脉功能障碍， 衍生的血管舒张通路（NO、PGI 2、EDHF）。为了实现这一目标，内皮衍生的 血管舒张通路将被阻断，血管功能将使用 动脉造影，然后使用RNA-seq，免疫印迹， 分光光度测定和酶活性测定。 我们的建议通过开发第一个机械框架来探索FASD研究的新前沿， 酗酒诱导的脑循环适应和在体内模型中识别酒精靶点。的 当前提案的目标与NIAAA 2017-2021年战略计划-目标1C一致，需要调查 循环系统;“产前酒精对器官有广泛的影响，包括循环系统.”

Prenatal alcohol exposure (PAE) can give rise to an array of irreversible damages to the developing fetus, known as fetal alcohol spectrum disorders (FASD). Alcohol's actions during pregnancy are complex and produce a myriad of heterogeneous outcomes that can affect nearly every fetal organ system. To date, no approved therapeutic drug exists for FASD, and the prevalence is estimated to be 3-9% in school-age children in the U.S. Despite nearly every brain region exhibiting vulnerability to PAE, a substantial knowledge gap persists regarding how PAE affects vascular function in the developing brain. Circulatory infrastructure develops concomitantly with the brain, and thus, impairment of brain circulatory function may result in altered nutrient, oxygen, metabolite, and hormone delivery to the brain during critical developmental windows. Delivery of these substrates is essential for proper neurodevelopment, and consequently, alcohol-induced disturbances of substrate delivery to the brain could have a profound effect on neurodevelopmental outcomes. In our established FASD rat model, we generated preliminary data utilizing high frequency ultrasonography in utero which showed that chronic binge PAE impairs middle cerebral artery blood flow and velocity time interval, a widely utilized indicator of resistance. The preliminary data further showed PAE resulted in impaired middle cerebral artery (MCA) agonist-induced dose-dependent vasodilation. In Aim 1, we will test if PAE will alter fetal cranially directed blood flow in our FASD model. To accomplish this aim, we will utilize non-invasive, ultra-high frequency ultrasonography to obtain color and pulse wave Doppler measurements of fetal heart rate, cardiac output, blood flow, and indices of vascular resistance in the major artery network that directly supplies blood to the brain (aorta, internal carotid, and MCA). Aim 2 will test if PAE will compromise the response to perfusion pressure in brain vasculature in early development. To accomplish this aim, we will cannulate the MCA, a major resistance artery that directly supplies the brain, and will assess if PAE-alters adaptations to pressure-dependent vascular responses. Aim 3 will test if PAE induces brain artery dysfunction through impairment of endothelial- derived vasodilatory pathways (NO, PGI2, EDHF). To accomplish this aim, combinations of endothelial-derived vasodilator pathways will be blocked pharmacologically and vascular function will be assessed using arteriography followed by assessment of vasodilatory pathways using RNA-seq, immunoblotting, spectrophotometric assays, and enzyme activity assays. Our proposal explores a new frontier of FASD research by developing the first mechanistic framework for binge alcohol-induced brain circulatory adaptations and identifying alcohol targets in an in vivo model. The current proposal's goals align with NIAAA strategic plan for 2017-2021 – Objective 1C, on the need to investigate the circulatory system; "prenatal alcohol has wide-ranging effects on organs, including the circulatory system…"