Fetal alcohol exposure and cerebrovascular development

胎儿酒精暴露与脑血管发育

• 批准号: 10582618
• 负责人: Anna Bukiya
• 金额: $ 43.58万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582618
• 关键词: 3-Dimensional; Adult; Affect; Alcohols; Animals; Arteries; Attention; Autopsy; Bioenergetics; Biological Assay; Biomedical Engineering; Birth; Blood flow; Brain; Brain Hypoxia-Ischemia; Brain hemorrhage; Brain imaging; Cells; Cerebrovascular Circulation; Cerebrovascular system; Cerebrum; Characteristics; Child; Collaborations; Computer software; Congenital Abnormality; Development; Developmental Delay Disorders; Diameter; Early Diagnosis; Embryo; Excision; Exhibits; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetus; Functional disorder; Genus Hippocampus; Goals; Human; Image; Image Analysis; Imaging Techniques; Infant; Intervention; Knowledge; Liver; Metabolic; Mitochondria; Morphology; Mus; Neurons; Nutritional; Organ; Outcome; Oxygen; Oxygen Consumption; Pharmacology; Pregnancy; Preventive measure; Proteome; Recording of previous events; Reporting; Research; Resolution; Rodent; Role; School-Age Population; Speed; System; Technology; Testing; Therapeutic Intervention; Three-Dimensional Image; Uncertainty; United States; Up-Regulation; Vascularization; Visualization; Work; alcohol exposure; alcohol response; cerebral artery; cerebrovascular; density; deoxyhemoglobin; effective therapy; extracellular; fetal; hemodynamics; high resolution imaging; image reconstruction; imaging approach; improved; in vivo fluorescence imaging; in vivo monitoring; maternal alcohol use; metabolic rate; neuron development; new therapeutic target; novel; optoacoustic tomography; photoacoustic imaging; reduce symptoms; response; sensor; therapeutically effective; three-dimensional visualization; tool; wasting

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.

在美国，胎儿酒精谱系障碍 (FASD) 是可预防的主要出生原因 缺陷和神经发育迟缓具有终生影响。 FASD 影响了大约 40,000 名婴儿 在美国，每年有 2-5% 的学龄儿童患有 FASD。目前，FASD的预测 怀孕期间没有这种方法，而且目前还没有针对 FASD 的现成治疗方法。人们普遍认为 早期发现 FASD 及其后续干预策略对于尽早、最大程度地进行干预至关重要 有效的治疗干预。虽然胎儿酒精暴露会针对多个器官和系统，但大脑 是受影响最严重的器官，表现出结构和功能异常。作为 神经元的发育关键取决于氧气输送、营养供应和废物清除 脑循环，近年来的研究越来越关注胎儿脑循环作为 孕产妇饮酒的关键目标。然而，控制胎儿的时间和机制 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 胎儿脑循环研究的进展缺乏高分辨率成像技术 适用于小型实验室动物物种的成像。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 光声断层扫描（PAT）将允许对一个胚胎中的所有胚胎进行非侵入性的同步可视化 小鼠子宫并纵向跟踪其成年期的发育，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 开发有效的治疗方法来缓解症状并制定针对 FASD 的预防措施是 对酒精相关靶点（包括胎儿脑动脉内的靶点）的了解相对有限。在 对此，目前的建议将集中在脑动脉线粒体上。线粒体的关键作用 调节脑动脉功能已有充分记录，毫无疑问，线粒体是其中之一 肝脏和神经元中显示的主要酒精传感器。在我们最近的开创性工作中，我们记录了 中期酒精暴露对胎儿大脑动脉蛋白质组的持续上调 怀孕。然而，针对产前反应的脑动脉线粒体改变的系统研究 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。为了克服该领域的这些障碍，我们建议完成三个相关的工作 目标：（1）优化用于啮齿动物3D高分辨率脑成像的高速PAT系统； (2) 我们 将开发先进的软件来改进 PAT 3D 图像重建和分析； (3) 我们将追踪 胎儿酒精暴露至成年后脑血管形态和功能的变化 重点关注胎儿脑血管密度、动脉直径和线粒体功能。