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

• 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
• 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

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.

通风的急性调整是维持动脉的强大稳态机制 和/或Brain P02，PC02和pH。通气控制中心的感觉反馈通过外围发生 和中央化学感受器，但是关于机制和 被认为是中央C02/pH化学感受器的神经元特异性亚群的相对重要性。 有什么赋予某些神经元的“感知” pH的固有能力？信号转移是什么 pH的途径？哪些神经元执行此任务？在哪些情况下，他们很重要（睡眠 清醒）？该提案的总体目标是解决有关中央的一些问题 通过利用具有固有固有的独特近交大鼠菌株的化学感受，C02的差异很大 灵敏度；棕色非线（BN：低响应者）和DAHL盐敏感（SS：高响应者）大鼠。第一的， 我们将确定BN大鼠C02敏感性的不足是否是由于细胞C02/pH敏感性降低所致 体外的个体化学敏感性神经元，这将通过转基因大鼠的发展有助于 在精选神经元池中表达荧光蛋白，用于直接斑块夹记录。我们也会 确定在具有这些神经元的脑干区域创建局灶性酸中毒的相对影响 BN和SS大鼠体内的亚群。最后，我们的初步数据表明多个 脑干中的神经调节剂可能有助于BN大鼠中钝化的C02敏感性，因此我们 将确定是否单独或集体增强这些神经调节剂是否可以恢复C02 BN大鼠的灵敏度。从这些独特的老鼠菌株中获得的数据将为您提供重要的见解 特定化学感受器亚群在调节Eupneic中的机制和相对重要性 通风和通气C02敏感性。他们还将提供有关呼吸有关疾病的见解， 并为未来的基因组研究提供框架，以识别遗传决定因素和 中央化学感受的独特细胞机制。