Fetal alcohol exposure and cerebrovascular development

在美国，胎儿酒精谱系障碍(FASD)是主要的可预防的出生原因 缺陷和神经发育迟缓，影响终生。据估计，每年有4万名婴儿受到FASD的影响 美国每年有2%-5%的学龄儿童患有FASD。目前，FASD的预测 在怀孕期间是不可用的，也没有现成的治疗FASD的方法。人们普遍认为 早期发现FASD及其随后的干预策略至关重要，以使最早和最 有效的治疗干预。虽然胎儿酒精暴露的目标是多个器官和系统，但大脑 构成了受影响最严重的器官，表现出结构和功能的异常。AS 神经元的发育关键取决于氧气的输送、营养的供应和废物的清除 脑循环，近年来的研究越来越重视胎儿脑循环作为一种 母亲饮酒的关键指标。然而，支配胎儿的时机和机制 脑血管对酒精的反应仍然难以捉摸。阻碍快速发展的主要障碍之一 胎儿脑循环的研究进展缺乏高分辨率的成像技术 适用于小型实验动物物种的成像。目前的提案是由合作团队提出的 生物工程师和脑血管生理学家的总体目标是提供高速3D 光声断层成像(PAT)将允许非侵入性的、同时显示 并纵向跟踪小鼠子宫和成年期的发育，以研究酒精与 暴露引起的胎儿血流动力学和出生后脑血管结局的变化。另一个障碍 开发有效的缓解症状的治疗方法和制定预防FASD的措施是一个 对酒精相关靶标的了解相对有限，包括胎儿大脑动脉内的靶标。在……里面 在这方面，目前的提案将重点放在脑动脉线粒体上。线粒体在细胞周期中的重要作用 调节大脑动脉的功能是有据可查的，线粒体无疑是其中之一。 酒精的主要感受器如肝脏和神经元所示。在我们最近的开创性工作中，我们记录了 酒精暴露对中期胎儿大脑动脉蛋白质组持续上调的影响 怀孕了。然而，对出生前脑动脉线粒体变化的系统研究 酒精暴露仍有待进行，酒精靶向胎儿大脑动脉线粒体的作用 仍有待确定。为了在实地克服这些障碍，我们建议完成三个相关的 目标：(1)我们将优化用于啮齿类动物3D高分辨率脑成像的高速PAT系统；(2)我们 将开发先进的软件，用于改进的PAT 3D图像重建和分析；(3)我们将跟踪 胎儿酒精暴露至成年期后脑血管形态和功能的变化 重点观察胎儿脑血管密度、动脉管径和线粒体功能。

In the United States, fetal alcohol spectrum disorders (FASD) represent the leading preventable cause of birth defects and neurodevelopmental delay with life-long implications. FASD affects an estimated 40,000 infants in the US each year, with 2-5% of younger school-age children having FASD. Currently, prediction of FASD during pregnancy is not available, and there are no readily available cures against FASD. It is widely believed that early detection of FASD and its subsequent intervention strategies are critical to allow earliest and most effective therapeutic interventions. While fetal alcohol exposure targets multiple organs and systems, the brain constitutes the most severely affected organ, exhibiting both structural and functional abnormalities. As neuronal development critically depends on the oxygen delivery, nutritional supply and waste removal by cerebral circulation, recent studies have been paying increasing attention to the fetal cerebral circulation as a critical target of maternal alcohol consumption. However, the timing and mechanisms that govern fetal cerebrovascular response to alcohol remain elusive. One of the major obstacles that preclude rapid advancement of the studies on fetal cerebral circulation is lack of high-resolution imaging technique that would be suitable for imaging of small lab animal species. Current proposal is put forth by the collaborating teams of bioengineers and cerebrovascular physiologists with the overall goal of delivering a high-speed 3D photoacoustic tomography (PAT) that will allow non-invasive, simultaneous visualization of all the embryos in a mouse utero and track their development into adulthood longitudinally to study the association between alcohol exposure-induced changes in fetal hemodynamics and cerebrovascular outcome after birth. Another obstacle to developing effective treatments to alleviate symptoms and develop preventive measures against FASD is a relatively limited knowledge on relevant targets for alcohol, including targets within fetal cerebral arteries. In this regard, current proposal will focus on cerebral artery mitochondria. Critical role of mitochondria in regulating cerebral artery function is well documented, and there is no doubt that mitochondrial is one of the major sensors for alcohol as shown in liver and neurons. In our recent pioneered work we documented persistent up-regulation of fetal cerebral artery proteome in response to alcohol exposure during mid- pregnancy. However, systematic studies on cerebral artery mitochondria alterations in response to prenatal alcohol exposure remain to be performed and the role of alcohol targeting of fetal cerebral artery mitochondria remains to be established. To overcome these obstacles in the field, we propose to complete three related Aims: (1) We will optimize a high-speed PAT system for 3D high-resolution brain imaging of rodents; (2) We will develop advanced software for improved PAT 3D image reconstruction and analysis; (3) We will trace cerebrovascular morphological and functional changes following fetal alcohol exposure into adulthood, with the focus on fetal cerebral vessel density, artery diameter and mitochondrial function.