Neuroplasticity and the carotid body

神经可塑性和颈动脉体

基本信息

批准号：
7586789
负责人：
ESTELLE B. GAUDA
金额：
$ 42.83万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-04-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7586789
关键词：
5&apos -Nucleotidase Acute Adenosine Adenosine A1 Receptor Adenosine Kinase Adenylate Cyclase Affect Afferent Neurons Animals Antioxidants Apnea Arousal Binding Biological Models Biosensor Bradycardia Breathing Carotid Body Cells Chemoreceptors Chronic Coupling Cytoprotection Data Development Environmental air flow Enzymes Equilibrium Event Exposure to Fiber Ganglia Gene Proteins Homocysteine Homocystine Human Hydrolase Hyperoxia Hypoxia Infant Label Lead Life Measures Mediating Metabolic Pathway Modeling Myxoid cyst NF-kappa B Neuromodulator Neuronal Plasticity Neurons Neurotransmitters Newborn Animals Nuclear Nucleotidases Nucleus solitarius Oxidative Stress Oxygen Oxygen measurement, partial pressure, arterial Pathway interactions Peripheral Physiological Premature Infant Preparation Production Purinergic P1 Receptors Reaction Reactive Oxygen Species Relative (related person)Research Personnel Respiratory Muscles Role Sensory Sensory Nerve Endings Signal Transduction Sleep Source Stress Subarachnoid Hemorrhage Sudden Death Synapses System Techniques Testing Toxic effect Type I Epithelial Receptor Cell Up-Regulation Ventilatory Depression adenosine deaminase afferent nerve attenuation body sense depressed extracellular high risk in vivo mature animal neuronal cell body neurotransmitter release novel nucleotidase postnatal postsynaptic programs protein expression receptor response rosin stressor success transcription factor vpr Genes

项目摘要

The peripheral arterial chemoreceptors in the carotid body are critical in regulating ventilation in response to changes in oxygen tension, and they provide essential sensory input during early development to stabilize and maintain breathing throughout life. Exposure to chronic hypoxia and hyperoxia (oxygen stress) during early postnatal development significantly depresses ventilatory responses to acute hypoxia in both newborn animals and human infants born prematurely. This ventilatory depression can be life-long in animals exposed to chronic hyperoxia and only partially reversible in animals exposed to chronic hypoxia during early postnatal development. Premature infants are particularly vulnerable to the effects of hyperoxia since antioxidant defenses are reduced. Furthermore, these infants are at high risk for persistent apnea and bradycardia, reduced arousal responses during sleep, and sudden death which are all adverse physiological events related to perturbations in chemoreceptor function. Adenosine modulates chemoreceptor activity and has been shown in other model systems to be critically important in mediating cytoprotection from oxidative stress. This proposal will test the overall hypothesis that oxygen stress (hypoxia and hyperoxia) during early postnatal development depends on the presence of functional adenosine A1 and A2a receptors on type 1 cells and sensory neurons in the carotid body, and the long term response of oxygen stress perturbs the balance of excitatory and inhibitory adenosine mechanisms resulting in decreased excitability of first order sensory neurons thereby blunting chemoreceptor responses. We will interrrogate this hypothesis with 3 specific aims that will determine the effect of development on 1) the functional neuoranatomy of the adenosine system in the carotid body, 2) the correlation between hypoxic induced adenosine and ATP release (measured with novel biosensors) with single-unit sensory nerve activity, 3) the perturbations induced by chronic hypoxic and hyperoxic exposure (in vivo) on both the ultrastructure of carotid body and alterations in the adenosine neuromodulator system, 4) the role of reactive oxygen species, nuclear factor - kB, and adenosine receptors in mediating hyperoxic induced cytotoxicty (ex vivo) in the carotid body and sensory neurons.

颈动脉体中的外周动脉化学感受器对于调节通风至关重要氧气张力的变化，它们在早期开发过程中提供了必要的感觉输入以稳定并在一生中保持呼吸。暴露于慢性缺氧和高氧（氧气）期间早期产后发育显着抑制两种新生儿急性缺氧的通气反应动物和人类婴儿过早出生。这种通风性抑郁症可以在暴露的动物中终身早期暴露于慢性缺氧的动物中，慢性高氧和仅部分可逆产后发展。早产婴儿特别容易受到高氧作用的影响抗氧化剂防御量减少。此外，这些婴儿有持续呼吸暂停的高风险心动过缓，睡眠期间的唤醒反应降低以及猝死都是不良生理的与化学感受器功能的扰动有关的事件。腺苷调节化学感受器的活性和在其他模型系统中已显示出对从氧化中介导细胞保护作用至关重要的压力。该提案将检验总体假设，即早期氧气（缺氧和高氧）产后发育取决于1型功能性腺苷A1和A2A受体的存在颈动脉体内的细胞和感觉神经元，氧气的长期反应使兴奋性和抑制性腺苷机制的平衡，导致一阶兴奋性降低感觉神经元因此使化学感受器反应变钝。我们将通过3 确定发展对1）功能性神经术的特定目的颈动脉体中的腺苷系统，2）低氧诱导的腺苷与ATP之间的相关性具有单单元感觉神经活动的释放（用新型生物传感器测量），3）扰动颈动脉的超微结构和腺苷神经调节剂系统的改变，4）活性氧的作用，核因子 - KB和腺苷受体中介导高氧化诱导的细胞毒性（Ex vivo）和颈体的腺苷受体和感觉神经元。