Neuroplasticity and the carotid body

神经可塑性和颈动脉体

• 批准号: 7176209
• 负责人: ESTELLE B. GAUDA
• 金额: $ 38.07万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/7176209
• 关键词: 5' -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; Chromosome Pairing; Chronic; Coupling; Cytoprotection; Data; Depressed mood; Development; Environmental air flow; Enzymes; Equilibrium; Event; Exposure to; Fiber; Fire - disasters; 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; Numbers; 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; Risk; Role; Sensory; Sensory Nerve Endings; Signal Transduction; Sleep; Source; Stress; Subarachnoid Hemorrhage; Sudden Death; Synapses; System; Techniques; Testing; Toxic effect; Transcriptional Activation; Type I Epithelial Receptor Cell; Up-Regulation; Ventilatory Depression; Week; adenosine deaminase; afferent nerve; attenuation; body sense; cytotoxicity; extracellular; in vivo; mature animal; neuronal cell body; neurotransmitter release; novel; nucleotidase; postnatal; postsynaptic; programs; protein expression; receptor; response; rosin; stressor; success; transcription factor

DESCRIPTION (provided by applicant): 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 interrogate 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 cytotoxicity (ex vivo) in the carotid body and sensory neurons.

描述（由申请人提供）：颈动脉体中的周围动脉化学感受器对于响应氧气张力的变化而调节通风至关重要，并且它们在早期发育过程中提供了必要的感​​觉输入，以稳定和维持整个生命的呼吸。早期发育期间患有慢性缺氧和高氧（氧气）的暴露会显着抑制新生动物和人类婴儿过早出生的急性缺氧的通气反应。这种通气性抑郁症可以是暴露于慢性高氧的动物中的生命，并且只能在产后早期发育期间暴露于慢性缺氧的动物​​中部分可逆。过早的婴儿特别容易受到高氧作用的影响，因为抗氧化剂的防御能力降低。此外，这些婴儿有持续性呼吸暂停和心动过缓的高风险，睡眠期间的唤醒反应降低以及猝死都是与化学感受器功能扰动有关的不良生理事件。腺苷调节化学感受器的活性，并已在其他模型系统中显示出对从氧化应激中介导细胞保护作用至关重要的。该提案将检验总体假设，即产后早期发育期间的氧应激（缺氧和高氧）取决于颈动脉体内功能性腺苷A1和A2A受体的存在，以及在颈动脉体内的感觉神经元的存在，以及氧气压力的长期响应，导致了兴奋性和抑制性抑制性良性的平衡，从而导致了降低的序列良好性，从而导致了抑制性良性的良性良好性。化学感受器反应钝。我们将以3个特定目的对这一假设进行审问，这些目标将决定发育对颈动脉体内腺苷系统的功能性神经术，2）低氧诱导的腺苷和ATP释放与ATP释放（用新型生物传感器测量的ATP释放）与单一感官感官的影响（3）抗炎（3）的敏感性（与持续性的疾病）相关性（3）颈动脉体的超微结构和腺苷神经调节剂系统的改变，4）活性氧，核因子-Kb和腺苷受体在颈动脉和感觉神经元中介导高氧化型细胞毒性（EX VIVO）中的作用。