Brain Circulatory Adaptations of Fetal Alcohol Spectrum Disorders

产前酒精暴露(PAE)会对发育中的胎儿造成一系列不可逆转的损害， 被称为胎儿酒精谱系障碍(FASD)。酒精在怀孕期间的行为是复杂的，会产生 无数不同的结局，几乎可以影响到每个胎儿器官系统。到目前为止，还没有批准 治疗FASD的药物已经存在，据估计，在美国学龄儿童中，FASD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，但仍然存在着巨大的知识鸿沟 关于PAE如何影响发育中大脑的血管功能。循环基础设施得到发展 与大脑相伴，因此，大脑循环功能的损害可能导致营养改变， 在关键的发育窗口期，氧气、代谢物和荷尔蒙向大脑输送。这些物品的交付 底物对于正常的神经发育是必不可少的，因此，酒精引起的神经功能障碍 向大脑输送底物可能会对神经发育结果产生深远影响。 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 宫内显示慢性暴饮性PAE损害大脑中动脉血流和血流速度时间间期， 一种被广泛使用的抗性指标。初步数据进一步显示，PAE导致中枢神经受损 大脑动脉(MCA)激动剂诱导的剂量依赖性血管扩张。在目标1中，我们将测试PAE是否会改变胎儿 我们的FASD模型中的头颅定向血流。为了实现这一目标，我们将利用非侵入性、超高 频率超声获得胎儿心率、心脏的彩色和脉搏波多普勒测量 输出量、血流量和主动脉网络中的血管阻力指数 大脑(大动脉、颈内动脉和大脑中动脉)。Aim 2将测试PAE是否会损害对灌注的反应 发育早期脑血管系统的压力。为了实现这一目标，我们将插管MCA，一个主要的 直接供应大脑的阻力动脉，将评估PAE是否改变了对压力依赖的适应 血管反应。AIM 3将测试PAE是否通过内皮损伤而导致脑动脉功能障碍 衍生的血管扩张通路(NO、PGI2、EDHF)。为了实现这一目标，内皮细胞衍生的组合 血管扩张剂通路将被药物阻断，血管功能将通过 动脉造影术之后使用RNA-SEQ，免疫印迹， 分光光度测定法和酶活力测定法。 我们的建议探索了FASD研究的新前沿，为FASD开发了第一个机械框架 在活体模型中，酗酒诱导的脑循环适应和识别酒精靶标。这个 当前提案的目标与NIAAA 2017-2021年战略计划--目标1C--关于调查的必要性保持一致 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…"