Chronic intermittent hyperoxia and development of respiratory control

慢性间歇性高氧和呼吸控制的发展

• 批准号: 8573596
• 负责人: RYAN W BAVIS
• 金额: $ 39.98万
• 依托单位: BATES COLLEGE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8573596
• 关键词: Adverse effects; Animal Model; Animals; Attenuated; Biomedical Research; Blood; Body Size; Brain-Derived Neurotrophic Factor; Breathing; Bronchopulmonary Dysplasia; Carbon Dioxide; Caring; Carotid Body; Cerebral Palsy; Chemoreceptors; Chronic; Clinical; Data; Development; Disease; Environmental air flow; Enzyme-Linked Immunosorbent Assay; Exposure to; Human; Hyperoxia; Hypoxemia; Hypoxia; Infant; Life; Low Birth Weight Infant; Mammals; Measures; Mediating; Medicine; Modeling; Molecular; Morphology; Neonatal; Neonatal Intensive Care Units; Neonatology; Outcome; Oxygen; Oxygen Therapy Care; Pathology; Patients; Pattern; Premature Birth; Premature Infant; Prevalence; Proteins; Publishing; Rattus; Records; Relative (related person); Reporting; Research; Retinopathy of Prematurity; Risk; Role; Signal Pathway; Signal Transduction; Specificity; Structure; Students; Sudden infant death syndrome; System; Testing; Time; Training; United States; Very Low Birth Weight Infant; adverse outcome; attenuation; clinical practice; clinically relevant; combat; common treatment; developmental plasticity; experience; improved; interest; novel; postnatal; prevent; public health relevance; research study; respiratory; response; undergraduate student

DESCRIPTION (provided by applicant): Supplemental O2 is among the most common treatments employed in neonatal intensive care units, particularly in the care of preterm and very low birth weight infants. Attempts are made to minimize O2 exposures, however, since hyperoxia may contribute to pathologies such as bronchopulmonary dysplasia, retinopathy of prematurity, and cerebral palsy. Despite these efforts, infants routinely experience episodes of hyperoxia during O2 therapy. Previous studies have shown that sustained exposures to hyperoxia have profound effects on respiratory control in developing mammals (smaller carotid bodies, reduced carotid body chemosensitivity, and attenuated hypoxic ventilatory responses (HVR)), but it is not known whether clinically relevant intermittent hyperoxia exposures elicit similar plasticity. Therefore, the primary objectives of the proposed research are to use a model of intermittent hyperoxia to study potential risks of O2 therapy to the developing respiratory control system and to explore mechanisms underlying any observed plasticity. Specific Aim 1 will test the hypothesis that chronic intermittent hyperoxia impairs the morphological and functional development of the carotid body, thereby diminishing normoxic and hypoxic ventilation. Guided by published records of O2 exposures in preterm infants, neonatal rats will be exposed to intermittent hyperoxia profiles (varying levels of O2 and/or CO2) for the first two postnatal weeks. Following these exposures, carotid body morphology, single-unit carotid chemoafferent responses to hypoxia, and ventilation will be assessed. The time course and developmental specificity of the observed plasticity will also be determined. Specific Aim 2 will test the hypothesis that chronic intermittent hyperoxia alters carotid body development through an activity- dependent mechanism that diminishes BDNF expression. Specifically, the effects of chronic intermittent hyperoxia on carotid body BDNF expression will be studied, and pharmacologic approaches will be used to manipulate BDNF signaling and carotid body activity to probe their roles in hyperoxia-induced plasticity. The proposed research is novel in focusing on developmental intermittent hyperoxia. The impact of chronic intermittent hyperoxia on respiratory control is virtually unknown despite the prevalence of hyperoxia in preterm infants and despite widespread recognition that other abnormal O2 exposures (e.g., sustained and intermittent hypoxia) have profound consequences for cardiorespiratory development. Thus, this model may have great significance for preterm infants exposed to periodic hyperoxia in the neonatal intensive care unit. If intermittent hyperoxia has adverse consequences for respiratory control, the model developed during this project period could be used to refine clinical practices and to explore preventative measures and therapies to improve patient outcomes. Undergraduate students will contribute to all aspects of the proposed research. Therefore, this project will also provide valuable training opportunities for talented students interested in biomedical research and medicine.

描述（由申请人提供）：补充氧气是新生儿重症监护室最常用的治疗方法之一，特别是在早产儿和极低出生体重婴儿的护理中。然而，人们试图尽量减少氧气暴露，因为高氧可能导致支气管肺发育不良、早产儿视网膜病变和脑瘫等疾病。尽管做出了这些努力，婴儿在 O2 治疗期间仍经常会出现高氧血症。先前的研究表明，持续暴露于高氧环境对发育中哺乳动物的呼吸控制具有深远影响（颈动脉体变小、颈动脉体化学敏感性降低以及缺氧通气反应（HVR）减弱），但尚不清楚临床相关的间歇性高氧暴露是否会引起类似的可塑性。因此，本研究的主要目标是使用间歇性高氧模型来研究氧气治疗对发育中的呼吸控制系统的潜在风险，并探索任何观察到的可塑性背后的机制。具体目标 1 将检验以下假设：慢性间歇性高氧会损害颈动脉体的形态和功能发育，从而减少正常氧和低氧通气。根据已发表的早产儿氧气暴露记录，新生大鼠将在出生后的前两周暴露于间歇性高氧环境（不同水平的氧气和/或二氧化碳）。在这些暴露之后，将评估颈动脉体形态、单单位颈动脉化学传入对缺氧的反应和通气。观察到的可塑性的时间进程和发育特异性也将被确定。具体目标 2 将检验以下假设：慢性间歇性高氧通过减少 BDNF 表达的活动依赖性机制改变颈动脉体发育。具体来说，将研究慢性间歇性高氧对颈动脉体 BDNF 表达的影响，并使用药理学方法来操纵 BDNF 信号和颈动脉体活动，以探讨它们在高氧诱导的可塑性中的作用。拟议的研究在关注发育性间歇性高氧方面具有新颖性。尽管高氧血症在早产儿中普遍存在，并且人们普遍认识到其他异常的氧气暴露（例如持续和间歇性缺氧）对心肺发育具有深远的影响，但慢性间歇性高氧血症对呼吸控制的影响实际上尚不清楚。因此，该模型对于新生儿重症监护病房中暴露于周期性高氧的早产儿可能具有重要意义。如果间歇性高氧对呼吸控制产生不利影响，则该项目期间开发的模型可用于完善临床实践并探索预防措施和疗法，以改善患者的预后。本科生将为拟议研究的各个方面做出贡献。因此，该项目也将为对生物医学研究和医学感兴趣的优秀学生提供宝贵的培训机会。