Redox Modulation of Nitric Oxide in Olfactory Dysfunction after Fetal Hypoxia

一氧化氮的氧化还原调节对胎儿缺氧后嗅觉功能障碍的影响

• 批准号: 7498975
• 负责人: SIDHARTHA TAN
• 金额: $ 18.94万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-20 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7498975
• 关键词: Acute; Address; Affect; Age; Animal Model; Animals; Antioxidants; Apoptosis; Attention; Biochemical Reaction; Biological Models; Blood - brain barrier anatomy; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Bypass; Calcium Channel; Cations; Cell Death; Cells; Cerebral Palsy; Cessation of life; Chemicals; Clinical; Development; Developmental Disabilities; Disease; Disruption; End Point; Fetus; Flow Cytometry; Functional Magnetic Resonance Imaging; Functional disorder; Gestational Age; Human; Hypoxia; Imaging Techniques; Injury; Invasive; Ions; Ischemia; Laboratories; Life; Lipid Peroxidation; Magnetic Resonance Imaging; Manganese; Measures; Mediating; Modeling; Modification; Monitor; Mothers; Motor; Neuraxis; Neurobiology; Neuronal Injury; Neurons; Newborn Animals; Nitric Oxide; Nitrogen; Obesity; Olfactory Epithelium; Olfactory tract; Oryctolagus cuniculus; Outcome; Oxidation-Reduction; Oxidative Stress; Oxygen; Pathology; Pathway interactions; Patients; Perinatal; Perinatal Brain Injury; Phenotype; Placental Insufficiency; Play; Production; Purpose; Reactive Nitrogen Species; Reactive Oxygen Species; Recovery; Recovery of Function; Regulation; Relative (related person); Research; Rest; Role; Sensory; Signal Transduction; Smell Perception; Stem cells; Study models; Superoxides; System; Taste Perception; Testing; Thinking; Time; Tyrosine; base; brain tissue; cell injury; concept; day; disability; fetal; fetus hypoxia; in vivo; innovation; interdisciplinary approach; interest; motor deficit; nitration; olfactory bulb; postnatal; prenatal; programs; repaired; response; sample fixation; uptake; voltage

DESCRIPTION (provided by applicant): One of the biggest problems of investigating oxidative stress and other mechanisms in the central nervous system is the lack of functional models that reflect the dynamic and living status of the intact animal. This problem is magnified for perinatal studies because the fetus is relatively inaccessible. This proposal introduces an innovative animal model system that uses the olfactory system as a window to the rest of the brain. It addresses the need of doing more studies investigating the effect of hypoxia on olfaction in the perinatal period. In patients with cerebral palsy (CP), sensory disabilities have not received as much attention as motor deficits and this provides a model for studying the issue of sensory disabilities among the postnatal developmental disabilities following fetal hypoxia-ischemia (H-I). Our hypothesis is that the interaction of reactive oxygen species (ROS) with nitric oxide mediates neuronal injury caused by fetal H-I. We will determine live olfactory neuron function in the intact animal using functional magnetic resonance imaging MRI that is based on the uptake of manganese ion in fetal H-I. Nitric oxide (NO) plays a central role in olfaction and is thought to do so by redox regulation with the formation of reactive nitrogen species (RNS). These concepts will be tested using a multidisciplinary approach in a recently developed animal model manifesting a CP phenotype following preterm uterine ischemia mimicking the clinical pathophysiology of acute placental insufficiency. We have previously shown that ROS and RNS are produced in fetal brain after H-I in this model, and administration of antioxidants to the mother ameliorates fetal brain injury. The first aim characterizes the developmental vulnerability of the olfactory tract to fetal H-I at various gestational ages. Functional MRI using manganese uptake will be correlated with cell injury, death and apoptosis by flow cytometry and immunohistochemical evidence in the olfactory epithelium and olfactory bulbs. The second aim determines if ROS and RNS mediate injury to the olfactory system caused by fetal H-I. We will test whether the developmental vulnerability is due to ROS by measuring superoxide and lipid peroxidation and/or RNS by S-nitrosylation and nitration of tyrosine. We will test our hypothesis by amelioration of the hypoxic-ischemic injury by decreasing ROS and manipulating levels of NO. The functional recovery of olfactory system will be assessed by serial functional MRI and separate immunostaining of mature olfactory neurons and olfactory bulbs at two postnatal ages. Our objectives are to understand key mechanisms of oxidative stress and redox signaling in neuronal injury from H-I and to ultimately generate the studies for an R-01application. This model system will be valuable in the study of other mechanisms of disease, plasticity, and recovery in the hitherto inaccessible fetus, and prenatal programming of smell in diverse pathologies, such as in obesity. The proposal introduces an innovative animal model system that uses the olfactory system as a window to the rest of the brain, addresses the need of doing more studies investigating sensory deficits such as olfaction in the perinatal period, and investigates a key mechanism of oxidative stress in olfactory injury. This model system will be valuable in the study of other mechanisms of disease, plasticity, and recovery in the hitherto inaccessible fetus and prenatal programming of smell in diverse pathologies.

描述（申请人提供）：研究中枢神经系统氧化应激和其他机制的最大问题之一是缺乏反映完整动物动态和生活状态的功能模型。这个问题在围产期研究中会被放大，因为胎儿相对难以接近。该提案引入了一种创新的动物模型系统，该系统使用嗅觉系统作为大脑其他部分的窗口。它满足了进行更多研究来调查围产期缺氧对嗅觉影响的需要。在脑瘫（CP）患者中，感觉障碍没有像运动缺陷那样受到重视，这为研究胎儿缺氧缺血（H-I）后出生后发育障碍中的感觉障碍问题提供了模型。我们的假设是活性氧 (ROS) 与一氧化氮的相互作用介导胎儿 H-I 引起的神经元损伤。我们将使用基于胎儿 H-I 中锰离子摄取的功能性磁共振成像 MRI 来确定完整动物的活体嗅觉神经元功能。一氧化氮 (NO) 在嗅觉中发挥着核心作用，人们认为它是通过氧化还原调节和活性氮物质 (RNS) 的形成来实现的。这些概念将使用多学科方法在最近开发的动物模型中进行测试，该模型表现出早产子宫缺血后的 CP 表型，模拟急性胎盘功能不全的临床病理生理学。我们之前已经表明，在该模型中，H-I 后胎儿大脑中会产生 ROS 和 RNS，并且向母亲施用抗氧化剂可改善胎儿脑损伤。第一个目标描述了不同胎龄的胎儿 H-I 的嗅道发育脆弱性。使用锰摄取的功能性 MRI 将通过流式细胞术和嗅上皮和嗅球中的免疫组织化学证据与细胞损伤、死亡和凋亡相关。第二个目标是确定 ROS 和 RNS 是否介导胎儿 H-I 引起的嗅觉系统损伤。我们将通过测量超氧化物和脂质过氧化和/或通过酪氨酸的 S-亚硝基化和硝化来测试发育脆弱性是否是由于 ROS 引起的。我们将通过减少 ROS 和控制 NO 水平来改善缺氧缺血性损伤来检验我们的假设。嗅觉系统的功能恢复将通过一系列功能性 MRI 以及对出生后两个年龄的成熟嗅觉神经元和嗅球的单独免疫染色进行评估。我们的目标是了解 H-I 神经元损伤中氧​​化应激和氧化还原信号传导的关键机制，并最终为 R-01 应用进行研究。该模型系统对于研究迄今为止无法接近的胎儿的疾病、可塑性和恢复的其他机制，以及各种病理学（例如肥胖症）的产前嗅觉编程将具有重要价值。该提案引入了一种创新的动物模型系统，该系统使用嗅觉系统作为大脑其他部分的窗口，满足了进行更多研究以调查围产期嗅觉等感觉缺陷的需要，并研究了嗅觉损伤中氧化应激的关键机制。该模型系统对于研究迄今为止无法接近的胎儿的疾病、可塑性和恢复的其他机制以及各种病理学中嗅觉的产前编程将是有价值的。