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（由申请人提供）：研究中枢神经系统中研究氧化应激和其他机制的最大问题之一是缺乏反映完好动物动态和生活状况的功能模型。由于胎儿相对无法访问，因此该问题被放大了围产期研究。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余部分的窗口。它解决了进行更多研究，以研究缺氧对围产期嗅觉的影响的更多研究。在脑瘫（CP）的患者中，感觉障碍的关注不如运动缺陷，这为研究胎儿缺氧 - 缺血性缺血（H-I）的产后发育障碍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了由胎儿H-I引起的神经元损伤。我们将使用基于胎儿H-I中锰离子的摄取，使用功能磁共振成像MRI来确定完整动物中的活嗅觉神经元功能。一氧化氮（NO）在嗅觉中起着核心作用，被认为是通过反应性氮种（RNS）形成的氧化还原调节来做到的。这些概念将在最近开发的动物模型中使用多学科方法进行测试，该模型表现出早产子宫缺血，模仿了急性胎盘不足的临床病理生理学。我们以前已经表明，在该模型中，H-I后在胎儿大脑中产生ROS和RN，而母亲的抗氧化剂可以改善胎儿脑损伤。第一个目的是在各种胎龄在胎儿H-I中嗅觉的发育脆弱性。使用锰摄取的功能性MRI将通过流式细胞仪和嗅觉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。第二个目标决定了ROS和RNS是否介导胎儿H-I引起的嗅觉系统的损伤。我们将通过测量超氧化物和脂质过氧化和/或RN来测试发育脆弱性是否是通过酪氨酸的S-硝基化和硝化作用引起的。我们将通过减少ROS和操纵NO的操纵水平来改善低氧 - 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串行功能性MRI评估，并在两个产后年龄在两个成熟的嗅觉神经元和嗅球的单独免疫染色。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 application产生研究。该模型系统将在迄今无法接近胎儿的其他疾病，可塑性和恢复其他机制以及各种病理学中的嗅觉编程（例如肥胖症中）中有价值。该提案介绍了一种创新的动物模型系统，该模型将嗅觉系统用作大脑其余部分的窗口，它解决了进行更多研究研究感觉缺陷（例如围产期嗅觉）的需求，并研究了嗅觉损伤中氧化应激的关键机制。该模型系统在研究迄今无法接近胎儿的其他疾病，可塑性和恢复机制方面将很有价值，以及各种病理学中气味的产前编程。