Brain Circulatory Adaptations of Fetal Alcohol Spectrum Disorders

胎儿酒精谱系疾病的脑循环适应

• 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
• 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

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）会导致发育中的胎儿一系列不可逆转的损害， 称为胎儿酒精谱系（FASD）。怀孕期间酒精的行为很复杂，生产 无数的异质结果会影响几乎每个胎儿器官系统。迄今为止，尚无批准 FASD的治疗药物存在，并且在美国的学龄儿童中估计为3-9％ 尽管几乎每个大脑区域都表现出对PAE的脆弱性，但大量知识差距仍然存在 考虑PAE如何影响发育中的大脑中的血管功能。循环基础设施的发展 同时与大脑同时，因此，脑循环功能的损害可能会导致营养变化， 在关键的发育窗口中，氧气，代谢物和马酮向大脑传递。交付这些 底物对于适当的神经发育至关重要，因此，酒精引起的灾难 向大脑的底物传递可能会对神经发育结果产生深远的影响。 在我们已建立的FASD大鼠模型中，我们利用高频超声检查生成了初步数据 在子宫中，这表明慢性bbinge pae会损害脑动脉血流和速度时间间隔， 广泛使用的电阻指标。进一步的数据进一步显示了PAE导致中间受损 大脑动脉（MCA）激动剂诱导的剂量依赖性血管舒张。在AIM 1中，我们将测试PAE是否会改变胎儿 在我们的FASD模型中，颅骨流动。为了实现这一目标，我们将利用非侵入性，超高 频率超声检查以获得胎儿心率，心率的颜色和脉搏波多普勒测量值 主要动脉网络中血管抗性的输出，血流和指标，直接将血液提供给 大脑（主动脉，内部颈动脉和MCA）。 AIM 2将测试PAE是否会损害对灌注的反应 早期发育中脑脉管系统的压力。为了实现这一目标，我们将插入MCA，这是一个专业 电阻动脉直接提供大脑，并将评估PAE脱位是否适应压力依赖性 血管反应。 AIM 3将测试PAE是否通过内皮损伤影响脑动脉功能障碍 派生的血管舒张途径（NO，PGI2，EDHF）。为了实现这一目标，内皮衍生的组合 血管扩张途径将被药物阻塞，并将使用血管功能进行评估 动脉造影，然后使用RNA-Seq，免疫印迹评估血管舒张途径， 分光光度测定和酶活性测定。 我们的建议通过开发第一个机械框架来探讨FASD研究的新领域 暴饮暴力引起的脑循环适应并在体内模型中鉴定酒精靶标。这 当前提案的目标与2017 - 2021年NIAAA战略计划一致 - 目标1C 电路系统； “产前酒精对器官（包括电路系统）具有广泛的影响……”