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（FASD）代表了可预防的生长延迟原因 儿童的神经发育迟缓。目前，没有任何可用的治疗方法 怀孕期间的意图或意外酒精暴露和导致的FASD。缺乏治疗 对策在很大程度上归因于缺乏对FASD发病机理的机械理解。尽管 产前酒精暴露（PAE）靶向多种组织类型和系统，大脑是最严重的 受影响器官。关于PAE文件病史异常的人类胎儿和婴儿的尸检病例 大脑的血管形成和缺氧缺血性神经元的变化或解决脑出血。继续工作 动物模型表明，平均80-85 mg/dl的生物血液酒精水平的PAE会扩张胎儿 体内脑动脉独立于全身循环，胎儿心脏功能，血脑屏障的变化，血脑屏障， 血液pH或PO2。预计扩张的胎儿脑动脉的病理生理意义将是 深刻的。首先，与酒精无关的病理学，自发的颅内低血压。 在临床上，由于脑血液速度下降而导致的儿童头骨的形态异常。 值得注意的是，颅面畸形是人类FASD的核心诊断标准。第二， 酒精诱导的胎儿脑动脉词典先于暴露的狒狒胎儿的生长延迟。第三， 在卵巢物种中，在暴露于PAE的大脑区域中观察到最大的神经元损失 酒精的最高脑血管改变。总共，临床和实验数据表明变化 在胎儿脑动脉中，直径可能在FASD的病理生理中起关键作用。胎儿的程度 脑血管成分对FASD发病机理的贡献尚待证明。像我们 最近报道的是，酒精引起的胎儿狒狒脑动脉的词典在体外被鸡尾酒完全消融 内源性大麻素受体1和2的阻滞剂（CB1和CB2）。当前的建议将利用 狒狒模型通过靶向胎儿酒精暴露的影响 欧洲央行脑动脉直径和胎儿生长延迟的系统。在Sub-aim 1.1中，我们将在体外使用 来自胎儿狒狒，选择性药物调节剂和质量的加压脑动脉 内生产生大麻素的光谱法检验了酒精诱导的词典的假设 胎儿脑动脉通过欧洲央行系统的不同成分介导。在Sub-aim 1.2中，我们将使用 CB受体的药理调节剂，体内非侵入性多普勒超声检查和液体 色谱 - 质谱法蛋白质组学，以检验以下假设。 欧洲央行系统在体内钝化酒精引起的胎儿脑动脉词典，并减少了生长延迟 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PAE的后果开发治疗学铺平道路。