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（FASD）代表了可预防的出生原因 缺陷和神经发育延迟具有终身影响。 FASD影响大约40,000名婴儿 美国每年，有2-5％的年轻学龄儿童患有FASD。目前，FASD的预测 在怀孕期间，没有针对FASD的容易获得的治疗方法。人们普遍相信 早期发现FASD及其随后的干预策略对于最早和大多数 有效的治疗干预措施。而胎儿酒精暴露靶向多个器官和系统，而大脑 构成最严重影响的器官，表现出结构和功能异常。作为 神经元的发育严重取决于通过 脑循环，最近的研究一直在越来越关注胎儿脑循环 孕妇饮酒的关键目标。但是，控制胎儿的时间和机制 对酒精的脑血管反应仍然难以捉摸。阻止快速的主要障碍之一 胎儿脑循环研究的进步是缺乏高分辨率成像技术 适合成像小实验室动物物种。当前的建议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）将允许无创，同时可视化所有胚胎 小鼠子宫并在纵向上跟踪成年后的发展，以研究酒精之间的关联 暴露引起的胎儿血流动力学和脑血管结局的变化。另一个障碍 开发有效治疗以减轻症状并针对FASD采取预防措施是一个 对酒精相关目标的知识相对有限，包括胎儿脑动脉内的靶标。在 这方面，当前的建议将集中于脑动脉线粒体。线粒体的关键作用 调节脑动脉功能已充分记录，毫无疑问，线粒体是其中之一 如肝脏和神经元所示，酒精的主要传感器。在我们最近的开创性工作中，我们记录了 胎儿脑动脉蛋白质组的持续上调，响应于中期期间的酒精暴露 怀孕。然而，对脑动脉线粒体改变产前的系统研究 酒精暴露仍有待进行，胎儿脑脑动脉线粒体的靶向作用 还有待确定。为了克服该领域的这些障碍，我们建议完成三个相关的 目的：（1）我们将优化用于3D高分辨率啮齿动物的高分辨率大脑成像的高速PAT系统； （2）我们 将开发用于改进PAT 3D图像重建和分析的高级软件； （3）我们将追踪 胎儿的形态学和功能变化，胎儿酒精暴露于成年期，与 专注于胎儿脑血管密度，动脉直径和线粒体功能。