Brain Circulatory Adaptations of Fetal Alcohol Spectrum Disorders

胎儿酒精谱系疾病的脑循环适应

基本信息

批准号：
10016074
负责人：
Emilie R Lunde
金额：
$ 3.57万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-30 至 2022-08-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10016074
关键词：
Acetylcholine Affect Agonist Alcohol consumption Alcohol-Induced Disorders Alcohols Animal Model Aorta Arteries Arteriographies Awareness Behavioral Biological Assay Blood Flow Velocity Blood Vessels Blood flow Brain Brain region Cardiac Output Cardiovascular system Cephalic Cerebrovascular Circulation Cerebrovascular system Cerebrum Child Chronic Cognitive Color Communities Complex Data Development Dimensions Disease model Dose Endothelium Epoprostenol Etiology Exhibits Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Fetal Development Fetal Heart Rate Fetal health Fetus Frequencies Functional disorder Goals Growth Hormones Human Immunoblotting Impairment Individual Infrastructure Internal carotid artery structure Intervention Investigation Knowledge Measurement Measures Mediating Metabolic Modeling Mothers National Institute on Alcohol Abuse and Alcoholism Neurobiology Neurons Nitric Oxide Nutrient Organ Outcome Oxygen Pathway interactions Perfusion Pharmaceutical Preparations Pharmacology Physiologic pulse Pregnancy Prevalence Prostaglandins I Rattus Regulation Reporting Research Resistance School-Age Population Schools Severities Strategic Planning Structure of umbilical artery Therapeutic Ultrasonography United States Variant Vascular blood supply Vascular resistance Vasodilation Vasodilator Agents adverse outcome alcohol exposure ascending aorta base body system brain circulation cerebral artery cerebrovascular design disability enzyme activity fetal fetal blood frontier hemodynamics improved in utero in vivo in vivo Model indexing insight middle cerebral artery neurobehavioral neurodevelopment neurodevelopmental effect neuronal survival novel novel strategies prenatal prenatal testing pressure prevent reduce symptoms reproductive response societal costs time interval transcriptome sequencing

项目摘要

Prenatal alcohol exposure (PAE) can give rise to an array of irreversible damages to the developing fetus, known as fetal alcohol spectrum disorders (FASD). Alcohol's actions during pregnancy are complex and produce a myriad of heterogeneous outcomes that can affect nearly every fetal organ system. To date, no approved therapeutic drug exists for FASD, and the prevalence is estimated to be 3-9% in school-age children in the U.S. Despite nearly every brain region exhibiting vulnerability to PAE, a substantial knowledge gap persists regarding how PAE affects vascular function in the developing brain. Circulatory infrastructure develops concomitantly with the brain, and thus, impairment of brain circulatory function may result in altered nutrient, oxygen, metabolite, and hormone delivery to the brain during critical developmental windows. Delivery of these substrates is essential for proper neurodevelopment, and consequently, alcohol-induced disturbances of substrate delivery to the brain could have a profound effect on neurodevelopmental outcomes. In our established FASD rat model, we generated preliminary data utilizing high frequency ultrasonography in utero which showed that chronic binge PAE impairs middle cerebral artery blood flow and velocity time interval, a widely utilized indicator of resistance. The preliminary data further showed PAE resulted in impaired middle cerebral artery (MCA) agonist-induced dose-dependent vasodilation. In Aim 1, we will test if PAE will alter fetal cranially directed blood flow in our FASD model. To accomplish this aim, we will utilize non-invasive, ultra-high frequency ultrasonography to obtain color and pulse wave Doppler measurements of fetal heart rate, cardiac output, blood flow, and indices of vascular resistance in the major artery network that directly supplies blood to the brain (aorta, internal carotid, and MCA). Aim 2 will test if PAE will compromise the response to perfusion pressure in brain vasculature in early development. To accomplish this aim, we will cannulate the MCA, a major resistance artery that directly supplies the brain, and will assess if PAE-alters adaptations to pressure-dependent vascular responses. Aim 3 will test if PAE induces brain artery dysfunction through impairment of endothelial- derived vasodilatory pathways (NO, PGI2, EDHF). To accomplish this aim, combinations of endothelial-derived vasodilator pathways will be blocked pharmacologically and vascular function will be assessed using arteriography followed by assessment of vasodilatory pathways using RNA-seq, immunoblotting, spectrophotometric assays, and enzyme activity assays. Our proposal explores a new frontier of FASD research by developing the first mechanistic framework for binge alcohol-induced brain circulatory adaptations and identifying alcohol targets in an in vivo model. The current proposal's goals align with NIAAA strategic plan for 2017-2021 – Objective 1C, on the need to investigate the circulatory system; "prenatal alcohol has wide-ranging effects on organs, including the circulatory system…"

产前酒精暴露（PAE）会对发育中的胎儿造成一系列不可逆转的损害，酒精在怀孕期间的作用非常复杂，并且会产生称为胎儿酒精谱系障碍 (FASD) 的疾病。无数异质的结果可能影响几乎每个胎儿器官系统。目前已有治疗 FASD 的药物，美国学龄儿童的患病率估计为 3-9% 尽管几乎每个大脑区域都表现出对 PAE 的脆弱性，但仍然存在巨大的知识差距关于 PAE 如何影响发育中的大脑的血管功能。与大脑同时发生，因此，大脑循环功能受损可能会导致营养物质，在关键的发育窗口期间将氧气、代谢物和激素输送到大脑。底物对于正常的神经发育至关重要，因此，酒精引起的神经功能紊乱向大脑输送底物可能对神经发育结果产生深远影响。在我们建立的 FASD 大鼠模型中，我们利用高频超声检查生成了初步数据子宫内慢性暴食 PAE 会损害大脑中动脉血流和速度时间间隔，广泛使用的阻力指标初步数据进一步显示 PAE 导致中层受损。脑动脉 (MCA) 激动剂引起的剂量依赖性血管舒张在目标 1 中，我们将测试 PAE 是否会改变胎儿。为了实现这一目标，我们将利用非侵入性的超高血流。频率超声检查获得胎心率、心脏的彩色和脉搏波多普勒测量结果直接供应血液的主要动脉网络的输出量、血流量和血管阻力指数目标 2 将测试 PAE 是否会损害对灌注的反应。为了实现这一目标，我们将在大脑中动脉（MCA）中插管，这是一个主要的部位。直接供应大脑的阻力动脉，并将评估 PAE 是否会改变对压力依赖性的适应目标 3 将测试 PAE 是否通过内皮损伤诱发脑动脉功能障碍。衍生的血管舒张途径（NO、PGI2、EDHF）为了实现这一目标，结合了内皮衍生的血管舒张途径。血管舒张途径将被药理学阻断，血管功能将使用评估动脉造影，然后使用 RNA-seq、免疫印迹评估血管舒张通路，分光光度测定和酶活性测定。我们的提案通过开发第一个机制框架来探索 FASD 研究的新领域酗酒引起的大脑循环适应并在体内模型中识别酒精目标。当前提案的目标与 NIAAA 2017-2021 年战略计划一致——目标 1C，需要进行调查循环系统；“产前酒精对器官有广泛的影响，包括循环系统……”