Fetal cerebral arteries and prenatal alcohol exposure

胎儿脑动脉和产前酒精暴露

• 批准号: 10590708
• 负责人: Anna Bukiya
• 金额: $ 60.94万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590708
• 关键词: Ablation; Accidents; Address; Affect; Alcohols; Animal Model; Area; Attention; Autopsy; Blood; Blood Vessels; Blood alcohol level measurement; Brain; Brain Hypoxia-Ischemia; Brain Ischemia; Brain hemorrhage; CNR1 gene; CNR2 gene; Cannabinoids; Cerebrovascular Circulation; Cerebrovascular system; Cerebrum; Child; Circulation; Clinical; Craniofacial Abnormalities; Data; Development; Diameter; Doppler Ultrasonography; Drops; Endocannabinoids; Excision; Exhibits; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Growth; Fetal Heart; Fetal Skull; Fetus; Functional disorder; Geographic Locations; Goals; Growth; Harvest; Head circumference; Human; In Vitro; Incidence; Individual; Infant; Intracranial Hypotension; Knowledge; Laboratories; Mass Spectrum Analysis; Mediating; Mental Retardation; Modeling; Modification; Morphology; Mothers; Neurons; Nutritional; Organ; Oxygen; Papio; Pathogenesis; Pathologic; Pathology; Pathway interactions; Play; Pregnancy; Prevalence; Proteomics; Recording of previous events; Reporting; Research; Role; Sheep; South Africa; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; United States; Vascularization; Vasodilation; Weight; Work; Youth; alcohol consumption during pregnancy; alcohol exposure; alcohol response; binge drinking; blood-brain barrier function; cerebral artery; cerebrovascular; cranium; diagnostic criteria; endogenous cannabinoid system; fetal; in vivo; liquid chromatography mass spectrometry; maternal alcohol use; mouse model; neuron apoptosis; neuron development; neuron loss; nonhuman primate; peer; pharmacologic; prenatal; pressure; receptor; response; therapeutic development; wasting

In the US, fetal alcohol spectrum disorders (FASD) represent the leading preventable cause of growth delay and neurodevelopmental retardation in children. Currently, there are no readily available cures against intended or accidental alcohol exposure during pregnancy and resulting FASD. This lack of therapeutic countermeasures is largely attributed to the lack of a mechanistic understanding of FASD pathogenesis. While prenatal alcohol exposure (PAE) targets multiple tissue types and systems, the brain is the most severely affected organ. Autopsy cases on human fetuses and infants with a history of PAE document abnormal vascularization of the brain and hypoxic-ischemic neuronal changes or resolving brain hemorrhage. Work on animal models demonstrates that PAE with maternal blood alcohol levels averaging 80-85 mg/dL dilates fetal cerebral arteries in vivo independent of changes in systemic circulation, fetal heart function, blood-brain barrier, blood pH, or pO2. The pathophysiological significance of dilated fetal cerebral arteries is expected to be profound. First, an alcohol‐unrelated pathology, spontaneous intracranial hypotension, is characterized clinically by morphological abnormalities of the child’s skull that result from a drop in cerebral blood velocity. Remarkably, craniofacial malformations serve as the central diagnostic criteria for FASD in humans. Second, alcohol-induced dilation of fetal cerebral arteries precedes the growth delay of exposed baboon fetuses. Third, in ovine species, the largest neuronal loss in response to PAE is observed in brain areas that exhibit the highest cerebrovascular alterations by alcohol. Altogether, clinical and experimental data suggest that changes in fetal cerebral artery diameter may play a critical role in the pathophysiology of FASD. The extent of the fetal cerebrovascular component contribution to the pathogenesis of FASD remains to be documented. As we recently reported, alcohol-induced dilation of fetal baboon cerebral arteries in vitro is fully ablated by a cocktail of blockers of the endocannabinoid receptors 1 and 2 (CB1 and CB2). The current proposal will utilize a baboon model to investigate the impact of fetal alcohol exposure by targeting the distinct components of the eCB system on fetal cerebral artery diameter and fetal growth delay. In sub-aim 1.1, we will use in vitro pressurized cerebral arteries from fetal baboons, selective pharmacological modulators, and mass spectrometry of endogenously produced cannabinoids to test the hypothesis that alcohol-induced dilation of fetal cerebral artery is mediated via distinct components of the eCB system. In sub-aim 1.2, we will use pharmacological modulators of CB receptors, non-invasive Doppler ultrasonography in vivo, and liquid chromatography-mass spectrometry proteomics to test the hypothesis that pharmacological blocking of the eCB system in vivo blunts alcohol-induced dilation of fetal cerebral arteries and diminishes the growth delay of fetal skull, brain, and vascular tissue. Characterization of the mechanism(s) that govern fetal cerebral artery responses to alcohol will pave the way for the development of therapeutics against consequences of PAE.

在美国，胎儿酒精谱系障碍（FASD）是导致生长迟缓的主要可预防原因 和儿童神经发育迟缓。目前，还没有现成的治疗方法， 怀孕期间有意或意外的酒精暴露和导致的FASD。缺乏治疗 因此，缺乏有效的治疗措施在很大程度上归因于缺乏对FASD发病机制的机械理解。而 产前酒精暴露（PAE）针对多种组织类型和系统，大脑是最严重的 受累器官。有PAE病史的人类胎儿和婴儿尸检病例记录异常 脑血管化和缺氧缺血性神经元变化或正在消退的脑出血。工作 动物模型表明，母体血液酒精水平平均为80-85 mg/dL的PAE使胎儿扩张， 脑动脉在体内的变化独立于体循环，胎儿心脏功能，血脑屏障， 血液pH或pO 2。扩张的胎儿脑动脉的病理生理学意义，预计将是 深刻首先，描述了与酒精无关的病理学，自发性颅内低血压， 临床上是由于脑血流速度下降导致的儿童颅骨形态异常。 值得注意的是，颅面畸形作为人类FASD的中心诊断标准。第二、 酒精诱导的胎儿脑动脉扩张先于暴露的狒狒胎儿的生长延迟。第三、 在绵羊种属中，在表现出以下特征的脑区域中观察到对PAE反应的最大神经元损失： 酒精对脑血管的影响最大总之，临床和实验数据表明， 胎儿大脑动脉直径可能在FASD的病理生理学中起关键作用。胎儿的程度 脑血管成分在FASD发病机制中的作用仍有待证实。正如我们 最近报道，酒精诱导的体外狒狒胎儿脑动脉扩张可被鸡尾酒完全消融 内源性大麻素受体1和2（CB 1和CB 2）的阻断剂。目前的建议将利用一个 狒狒模型研究胎儿酒精暴露的影响，针对不同的成分， eCB系统对胎儿脑动脉直径和胎儿生长延迟的影响。在子目标1.1中，我们将使用体外 来自胎儿狒狒的加压脑动脉、选择性药理学调节剂和质量 内源性产生的大麻素的光谱分析，以测试酒精诱导的扩张的假设， 胎儿脑动脉通过eCB系统的不同组分介导。在子目标1.2中，我们将使用 CB受体的药理学调节剂、体内非侵入性多普勒超声检查和液体 色谱-质谱蛋白质组学来测试药理学阻断的假设， 体内eCB系统可减弱酒精诱导的胎儿脑动脉扩张， 胎儿头骨大脑和血管组织控制胎儿脑动脉的机制的表征 对酒精的反应将为开发针对PAE后果的治疗方法铺平道路。