Roles of peripheral and central respiratory chemoreceptors in inbred rat strains

呼吸机的急性调整是维持动脉的一种强大的体内平衡机制 和/或脑P02、PC02和pH。通过外周感觉反馈到呼吸机控制中心 和中枢化学感受器，但关于其机制和 被认为是中枢C02/pH化学感受器的特定神经元亚群的相对重要性。 是什么赋予精选神经元“感知”PH值的内在能力？什么是信号转导？ 酸碱度的途径？哪些神经元执行这项任务？在什么情况下它们是重要的(睡眠 清醒)？这项提案的总体目标是解决其中一些关于中央 利用独特的近交系大鼠品系的化学感受，这些品系具有固有的和巨大的二氧化碳差异 敏感度：Brown Nonway(BN：低反应者)和Dahl盐敏感性(SS：高反应者)大鼠。第一, 我们将确定BN大鼠对二氧化碳敏感性的缺陷是否是由于细胞对二氧化碳/pH敏感性的降低 体外分离的化疗敏感神经元，将有助于转基因大鼠的发育 在选定的神经元池中表达荧光蛋白，用于直接膜片钳记录。我们还将 确定在含有这些神经元的脑干区域造成局灶性酸中毒的相对影响 BN和SS大鼠体内亚群的变化。最后，我们的初步数据表明，赤字在多个方面 脑干中的神经调节剂可能有助于BN大鼠对二氧化碳的钝化敏感性，因此我们 将确定单独或共同增加这些神经调节剂是否可以恢复二氧化碳 BN大鼠的敏感性。从这些独特的老鼠品系中获得的数据将为 特定化学感受器亚群调节优势性的机制及其相对重要性 通风和通风对二氧化碳的敏感性。它们还将提供对与呼吸相关的疾病的见解， 并为未来的基因组研究提供了一个框架，旨在确定遗传决定因素和 中枢化学接收发生的独特的细胞机制。

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.