Mechanism of perinatal-hyperoxic suppression of chemoreceptor function

围产期高氧抑制化学感受器功能的机制

• 批准号: 7319148
• 负责人: DAVID F. DONNELLY
• 金额: $ 39.5万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-05 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7319148
• 关键词: Accounting; Acute; Address; Adenosine; Adult; Altitude; Animals; Arousal; Axon; Birth; Blood; Blood Pressure; Breathing; Calcium; Candidate Disease Gene; Cardiovascular system; Carotid Body; Catecholamines; Cell secretion; Cells; Characteristics; Chemoreceptors; Chromogranin A; Closure; Complementary DNA; Coupling; Cytoplasmic Granules; Data; Development; Disruption; Elements; Environment; Exposure to; Gene Chips; Gene Expression; Genes; Glomus Cell; Glossopharyngeal nerve structure; Goals; Heart Diseases; Hyperoxia; Hypoxia; Immunohistochemistry; Impairment; In Vitro; Intervention; Ion Channel; Laboratories; Life; Measurement; Mediating; Membrane Potentials; Messenger RNA; Mutation; Nerve; Nerve Endings; Neurons; Newborn Infant; Numbers; Organ; Osmotic Shocks; Oxygen; Oxyhemoglobin; Pathway interactions; Pattern; Perinatal; Peripheral; Physiological; Polymerase Chain Reaction; Premature Infant; Property; Publishing; Purpose; Rattus; Reflex action; Research Personnel; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Secretory Component; Secretory Vesicles; Signal Transduction; Site; Sleep; Small Interfering RNA; Stimulus; Tachykinin; Technology; Testing; Time; Tissues; Universities; Vesicle; Week; Work; afferent nerve; base; carotid sinus; chromaffin granule amine transporter; critical developmental period; experience; in utero; postnatal; presynaptic; rapid detection; receptor; research study; respiratory; response; sensor

DESCRIPTION (provided by applicant): Carotid body chemoreceptors are the primary sensors of the respiratory/cardiovascular system for the rapid detection of hypoxia (low blood oxygen). Their stimulation initiates a number of protective reflexes, including an increase in drive to breathe, arousal from sleep and increased blood pressure. Previous, published results demonstrated that exposure to hyperoxia (high blood oxygen) during critical periods in the time immediately after birth results in an impaired ventilatory response to acute hypoxia, an impairment that lasts throughout life, despite a return to normal levels of oxygen. The purpose of our proposed study is to identify the mechanism by which hyperoxia exposure results in impaired chemoreceptor function. Work from our laboratories demonstrate that hyperoxia exposure results in a large decrease in afferent nerve activity during normoxia and during acute hypoxia exposure. The impaired oxygen sensing appears due to alterations in the function of glomus cells - cells presynaptic to the afferent nerve endings and which are generally believed to be the site of transduction of hypoxia. Gene chip analysis (and confirmation by real-time, semi-quantitative PCR) demonstrate that hyperoxia reduces expression of multiple genes involved in the synthesis of secretory granules and reduces expression of some ion channels which are proposed to be involved in hypoxia-mediated depolarization of glomus cells, specifically TASK-1 and TASK-3. Furthermore, the depolarization and secretory responses of glomus cells to acute hypoxia are reduced by hyperoxia exposure. The proposed studies will examine the time course of genetic changes and correlate this with changes in organ function as assessed by secretion (voltammetry), organ function (spiking activity on single axons) and biophysical responses to hypoxia of glomus cells (depolarization, calcium responses). Identification of genes critical for organ function and which are altered by hyperoxia will be assessed by gene chip analyses and confirmation by PCR and quantitative immunohistochemistry. Confirmation of function will be undertaken using siRNA suppression of candidate genes. The anticipated results will identify critical elements within peripheral chemoreceptors which are altered by perinatal hyperoxia. Since hyperoxia is extensively used clinically in newborn and, especially in premature infants, these results are important in understanding physiologic alterations caused by this intervention.

描述（由申请人提供）：颈动脉体化学感受器是快速检测缺氧（低血氧）的呼吸/心血管系统的主要传感器。他们的刺激引发了许多保护反射，包括增加呼吸动力，唤醒睡眠和血压升高。以前发表的结果表明，在出生后立即在关键时期内暴露于高氧（高血氧）会导致对急性缺氧的通气反应受损，尽管氧气恢复正常，但这种损害会持续一生。我们提出的研究的目的是确定高氧暴露导致化学感受器功能受损的机制。我们实验室的工作表明，高氧暴露导致正常氧和急性低氧期间传入神经活性大大降低。氧气感应受损是由于Glomus细胞的功能改变 - 突触前向传入神经末端的细胞的功能改变，通常认为这是缺氧转导的部位。基因芯片分析（并通过实时，半定量PCR进行证实）表明，高氧降低了与分泌颗粒合成的多个基因的表达，并降低了一些离子通道的表达，这些离子通道的表达涉及低氧介导的肾小球细胞的去极化，这些离子通道的表达，特定任务1和任务-3。此外，肾小球细胞对急性缺氧的去极化和分泌反应通过高氧暴露降低。拟议的研究将检查遗传变化的时间过程，并将其与通过分泌（伏安法），器官功能（单轴突上的峰值活性）评估的器官功能的变化以及对Glomus细胞缺氧（去极化，钙反应）的生物物理反应进行评估。对器官功能至关重要的基因的鉴定，并且通过高氧改变了基因，将通过基因芯片分析和通过PCR和定量免疫组织化学进行确认。将使用siRNA抑制候选基因进行功能确认。预期的结果将确定周围化学感受器中的关键因素，这些因素会因围产期高氧而改变。由于高氧在新生儿临床上广泛使用，尤其是在早产儿中，因此这些结果对于理解由这种干预引起的生理改变很重要。