Fetal cerebral arteries and prenatal alcohol exposure

胎儿脑动脉和产前酒精暴露

基本信息

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
项目类别：
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

项目摘要

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目前，尚无现成的治疗方法。怀孕期间故意或意外接触酒精并导致 FASD 缺乏治疗。对策很大程度上归因于缺乏对 FASD 发病机制的认识。产前酒精暴露（PAE）针对多种组织类型和系统，其中大脑最为严重有 PAE 病史的人类胎儿和婴儿的尸检病例记录异常。大脑血管化和缺氧缺血性神经元变化或解决脑出血。动物模型表明，母体血液酒精水平平均为 80-85 mg/dL 时，PAE 会导致胎儿扩张体内脑动脉独立于体循环、胎心功能、血脑屏障的变化，血液 pH 值或 pO2 胎儿脑动脉扩张的病理生理学意义预计为首先，其特征是一种与酒精无关的病理，即自发性颅内低血压。临床上是由于脑血流速度下降导致儿童颅骨形态异常。值得注意的是，颅面畸形是人类 FASD 的核心诊断标准。酒精引起的胎儿脑动脉扩张先于暴露的狒狒胎儿的生长延迟。在绵羊物种中，在表现出 PAE 反应的大脑区域中观察到最大的神经损失总而言之，临床和实验数据表明，酒精对脑血管的影响最大。胎儿大脑动脉直径可能在 FASD 的病理生理学中起关键作用。脑血管成分对 FASD 发病机制的贡献仍有待记录。最近报道，酒精引起的胎儿狒狒大脑动脉的体外扩张被鸡尾酒完全消融内源性大麻素受体 1 和 2（CB1 和 CB2）的阻断剂目前的提案将利用狒狒模型通过针对酒精的不同成分来研究胎儿酒精暴露的影响 eCB 系统对胎儿大脑动脉直径和胎儿生长延迟的影响在子目标 1.1 中，我们将在体外使用。来自胎儿狒狒的加压脑动脉、选择性药理调节剂和质量内源性产生的大麻素的光谱测定，以检验酒精引起的大麻素扩张的假设胎儿大脑动脉是通过 eCB 系统的不同组成部分介导的。在子目标 1.2 中，我们将使用。 CB受体的药理调节剂、体内无创多普勒超声检查和液体色谱-质谱蛋白质组学来检验药物阻断的假设 eCB 系统在体内减弱酒精引起的胎儿脑动脉扩张并减少胎儿生长迟缓胎儿颅骨、大脑和血管组织的特征控制胎儿脑动脉的机制。对酒精的反应将为开发针对 PAE 后果的疗法铺平道路。