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Roles of peripheral and central respiratory chemoreceptors in inbred rat strains

外周和中枢呼吸化学感受器在近交系大鼠品系中的作用

基本信息

批准号：
8515505
负责人：
Matthew Robert Hodges
金额：
$ 22.58万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8515505
关键词：
Acidosis Acute Address Adult Affect Attention Biological Models Blood gas Brain Brain Stem Breathing Carbon Dioxide Carotid Body Cell Nucleus Chemoreceptors Dahl Hypertensive Rats Data Dependence Development Disease Dopamine Environmental air flow Exercise Exhibits Functional disorder Future Genetic Determinism Genomics Goals High Pressure Liquid Chromatography Homeostasis Human Hypoxia In Vitro Inbred Strains Rats Inbreeding Individual Instruction Investigation Lesion Light Lung diseases Maintenance Measures Microdialysis Modeling Monoamine Oxidase A Neuromodulator Neurons Norepinephrine Peripheral Proteins Rat Strains Rattus Recovery Regulation Relative (related person)Rest Role Selective Serotonin Reuptake Inhibitor Serotonin Signal Transduction Pathway Sleep Slice Solutions Sudden infant death syndrome Syndrome Tissues Transgenic Organisms Update Variant Wakefulness design dopamine transporter extracellular human disease in vivo inhibitor/antagonist insight neuroregulation pH Homeostasis patch clamp pup research study respiratory response reuptake salt sensitive sensory feedback

项目摘要

Acute adjustments in ventilation represent a powerful homeostatic mechanism for the maintenance of arterial and/or brain P02, PC02 and pH. Sensory feedback to the ventilatory control centers occurs via peripheral and central chemoreceptors, but there are several unresolved questions regarding the mechanisms and relative importance of specific subpopulations of neurons thought to act as central C02/pH chemoreceptors. What confers upon select neurons the intrinsic ability to "sense" pH? What are the signal transduction pathways for pH? Which neurons perform this task? Under which circumstances are they important (sleep wakefulness)? The overall goals of this proposal are to address some of these questions regarding central chemoreception by taking advantage of unique inbred rat strains with inherent, and large differences in C02 sensitivity; the Brown Nonway (BN: low responder) and Dahl Salt-sensitive (SS: high responder) rats. First, we will determine if the deficit in C02 sensitivity in BN rats is due to decreased cellular C02/pH sensitivity of individual chemosensitive neurons in vitro, which will be aided by the development of transgenic rats expressing fluorescent proteins in select neuron pools for direct patch clamp recordings. We will also determine the relative effects of creating focal acidosis in brainstem regions harboring these neuronal subpopulations in BN and SS rats in vivo. Finally, our preliminary data suggests that deficits in multiple neuromodulators in the brainstem may contribute to the blunted C02 sensitivity in the BN rats, and thus we will determine whether if augmenting these neuromodulators individually or collectively can restore C02 sensitivity in the BN rat. The data obtained from these unique rat strains will provide significant insights into the mechanisms and relative importance of specific chemoreceptor subpopulations in regulating eupneic ventilation and ventilatory C02 sensitivity. They will also provide insights into respiratory-related diseases, and provide a framework for future genomic investigations aimed at identifying the genetic determinants and the unique cellular mechanisms by which central chemoreception occurs.

通气的急性调整代表了维持动脉血流的强大稳态机制。和/或脑 P02、PC02 和 pH。通气控制中心的感觉反馈通过外围设备发生和中枢化学感受器，但关于其机制和作用还有几个未解决的问题被认为充当中央 CO2/pH 化学感受器的特定神经元亚群的相对重要性。是什么赋予了选定的神经元“感知”pH 值的内在能力？信号传导有哪些 pH值的途径？哪些神经元执行此任务？在什么情况下它们很重要（睡眠清醒）？该提案的总体目标是解决其中一些有关中央的问题通过利用具有固有的、巨大的CO2差异的独特近交系大鼠品系来实现化学感受敏感性； Brown Nonway（BN：低反应者）和 Dahl 盐敏感（SS：高反应者）大鼠。第一的，我们将确定 BN 大鼠的 CO2 敏感性缺陷是否是由于细胞 CO2/pH 敏感性降低所致体外单个化学敏感神经元，这将通过转基因大鼠的发育得到帮助在选定的神经元池中表达荧光蛋白以进行直接膜片钳记录。我们还将确定在包含这些神经元的脑干区域中产生局灶性酸中毒的相对影响 BN 和 SS 大鼠体内亚群。最后，我们的初步数据表明，多个国家的赤字脑干中的神经调节剂可能导致 BN 大鼠 CO2 敏感性减弱，因此我们将确定单独或共同增强这些神经调节剂是否可以恢复二氧化碳 BN 大鼠的敏感性。从这些独特的大鼠品系获得的数据将为以下方面提供重要的见解：特定化学感受器亚群在调节 eupneic 中的机制和相对重要性通气和通气CO2 敏感性。他们还将提供有关呼吸系统相关疾病的见解，并为未来的基因组研究提供一个框架，旨在确定遗传决定因素和中枢化学感受发生的独特细胞机制。