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

基本信息

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
项目类别：
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

项目摘要

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呼吸/心血管系统的主要传感器，用于快速检测缺氧（低血氧）。它们的刺激会引发许多保护性反射，包括呼吸动力的增加、睡眠中的觉醒和血压升高。先前发表的结果表明，在出生后的关键时期暴露于高氧（高血氧）会导致对急性缺氧的通气反应受损，尽管氧气水平恢复到正常水平，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，在常氧和急性缺氧期间，高氧暴露会导致传入神经活动大幅下降。氧感应受损是由于球细胞功能的改变而出现的，球细胞是传入神经末梢突触前的细胞，通常被认为是缺氧转导的部位。基因芯片分析（并通过实时半定量 PCR 进行确认）表明，高氧会降低参与分泌颗粒合成的多个基因的表达，并降低一些离子通道的表达，这些离子通道被认为与缺氧介导的去极化有关。血管球细胞，特别是 TASK-1 和 TASK-3。此外，高氧暴露会降低血管球细胞对急性缺氧的去极化和分泌反应。拟议的研究将检查遗传变化的时间进程，并将其与通过分泌（伏安法）、器官功能（单个轴突上的尖峰活动）和血管球细胞对缺氧的生物物理反应（去极化、钙反应）评估的器官功能变化相关联。。将通过基因芯片分析评估对器官功能至关重要且因高氧而改变的基因的鉴定，并通过 PCR 和定量免疫组织化学进行确认。将使用候选基因的 siRNA 抑制来确认功能。预期结果将确定外周化学感受器内因围产期高氧而改变的关键元件。由于高氧在临床上广泛用于新生儿，尤其是早产儿，因此这些结果对于理解这种干预引起的生理变化非常重要。