Outcome of Neurological Disorders in Adults Exposed to Moderate Levels of Alcohol in Utero

子宫内接触适量酒精的成人神经系统疾病的结果

• 批准号: 10655859
• 负责人: Surojit Paul
• 金额: $ 41.13万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655859
• 关键词: Address; Adult; Adult Children; Adverse effects; Affect; Age; Alcohol abuse; Alcoholism; Alcohols; Antioxidants; Attenuated; Behavioral; Biochemical; Blood alcohol level measurement; Brain; Brain Diseases; Brain Injuries; Brain region; CX3CL1 gene; Characteristics; Child; Chronic; Clinical; Cognitive; Communication; Compensation; Consumption; Control Groups; Country; Craniofacial Abnormalities; Data; Dimerization; Dinoprostone; Disease; Electron Spin Resonance Spectroscopy; Etiology; Evaluation; Exposure to; Female; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Alcohol Syndrome; Fetal Development; Fetus; Flow Cytometry; Generations; Glutathione; Glutathione Metabolism Pathway; Growth; Health; Homeostasis; Imaging Techniques; Impairment; Infarction; Inflammatory; Inflammatory Response; International; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Knockout Mice; Knowledge; Life; Link; Longevity; Magnetic Resonance Imaging; Middle Cerebral Artery Occlusion; Mission; Molecular; Mus; Neuroimmune; Neurologic; Neurological outcome; Neurons; Neuroprotective Agents; Newborn Infant; Outcome; Oxidative Stress; Pattern; Peptides; Peripheral; Pharmacology Study; Predisposition; Pregnancy; Pregnant Women; Premature Mortality; Prostaglandins; Protein Tyrosine Phosphatase; Public Health; Reactive Oxygen Species; Recommendation; Research; Risk; Severities; Signal Pathway; Signal Transduction; System; Testing; Up-Regulation; aged; alcohol consumption during pregnancy; alcohol measurement; behavior test; binge drinking; chemokine; disability; drinking; excitotoxicity; experimental study; functional outcomes; glial activation; immune cell infiltrate; in utero; loss of function; male; maternal alcohol use; middle age; mouse model; nervous system disorder; neurobehavioral; neurodevelopment; neuroprotection; novel; offspring; peptidomimetics; prenatal exposure; programs; restoration; sex; social

Project Summary / Abstract Heavy maternal alcohol consumption during pregnancy is known to interfere with normal fetal development and is the leading cause of disabilities and premature mortality in children. On the other hand, moderate level of maternal alcohol consumption (blood alcohol concentration < 0.08%) is thought to be less disruptive to neurodevelopment. However, it is still unclear whether such moderate prenatal alcohol exposure (PAE) has any adverse effect on the brain function of the adult offspring. Our preliminary data now indicate that moderate PAE could lead to depletion of endogenous glutathione (GSH) level in the brain of the adult mice offspring and also diminish the function of a brain-enriched and neuron-specific tyrosine phosphatase, STEP that has been shown to be involved in neuroprotection against excitotoxic insults. The preliminary data also provide compelling evidence that a mild ischemic insult in adult PAE offspring leads to exacerbation of ischemic brain injury and is associated with up regulation of inflammatory response in the brain. These findings raise the possibility that moderate PAE has a life-long impact on the antioxidant defense system in the brain of the offspring. The resulting higher basal level of oxidative stress could compromise the ability of the brain to compensate when exposed to a neurological insult in later stages of life leading to augmentation of brain damage. To test this novel hypothesis, in Aim 1 we propose to evaluate the impact of moderate PAE on the synthesis and turnover of GSH, generation of reactive oxygen species and function of STEP in different brain regions of adult, middle-aged and aged PAE mice offspring. Our approach will include the non-invasive Electron Paramagnetic Resonance (EPR) imaging technique and a multitude of molecular and biochemical studies, utilizing both male and female PAE offspring with age-matched non-PAE control group. The proposed studies in Aim 2 will utilize magnetic resonance imaging (MRI) and a battery of behavioral tests for noninvasive and longitudinal evaluation of the progression and severity of ischemic brain damage in adult and aged PAE mice offspring from both sexes. These studies will further evaluate whether loss of function of STEP could contribute to the exacerbation of ischemic brain injury in PAE offspring. At the molecular level, the proposed studies in Aim 3 will further delineate the causal link between the high basal level of oxidative stress and exacerbation of ischemic brain injury in both male and female PAE offspring. Our approach will utilize flow cytometry, quantitative PCR, immunohistochemical and pharmacological studies, as well as multiple knockout mice. The proposed research is significant since it will addresse a significant gap in our knowledge on the life-long health risks of moderate alcohol consumption during pregnancy.

项目摘要 /摘要 众所周知，怀孕期间大量的孕妇饮酒会干扰正常的胎儿发育和 是儿童残疾和过早死亡的主要原因。另一方面，中等水平 孕产妇饮酒（血液酒精浓度<0.08％）被认为不那么破坏 神经发育。但是，尚不清楚这种适度的产前酒精暴露（PAE）是否有任何 对成人后代的大脑功能的不利影响。我们的初步数据现在表明中等PAE 可能导致成年小鼠后代大脑中内源性谷胱甘肽（GSH）水平的耗竭 减少脑增强和神经元特异性酪氨酸磷酸酶的功能，已显示 参与针对兴奋性毒性损伤的神经保护作用。初步数据还提供了引人注目的 有证据表明，成年后后代的轻度缺血性侮辱会导致缺血性脑损伤加剧，并且IS 与大脑中炎症反应的调节有关。这些发现增加了 中等PAE对后代大脑中的抗氧化防御系统产生了长期的影响。结果 较高的基础氧化应激水平可能会损害大脑在暴露于 在生命的后期，神经系统侮辱导致脑损伤的增强。为了检验这个新的假设， 在AIM 1中，我们建议评估中等PAE对GSH的合成和营业额的影响 成年，中年和老化的不同大脑区域的活性氧和步骤的功能 老鼠后代。我们的方法将包括非侵入电子顺磁共振（EPR）成像 技术以及许多分子和生化研究，都利用男性和雌性Pae后代 与年龄匹配的非PAE对照组。 AIM 2中提出的研究将利用磁共振成像 （MRI）和一系列行为测试，用于非侵入性和纵向评估的进展和严重性评估 两性的成年和老年PAE小鼠的缺血性脑损伤。这些研究将进一步 评估步骤功能丧失是否会导致PAE缺血性脑损伤的加剧 后代。在分子水平上，AIM 3中提出的研究将进一步描述 雄性和雌性PAE的缺血性脑损伤的高基础氧化应激水平和加剧 后代。我们的方法将利用流式细胞仪，定量PCR，免疫组织化学和药理学 研究以及多个淘汰小鼠。拟议的研究很重要，因为它将解决重大的 我们对怀孕期间适度饮酒的终身健康风险的了解差距。