Roles of peripheral and central respiratory chemoreceptors in inbred rat strains

通气的急性调整代表了维持动脉血流的强大的稳态机制。 和/或脑P02、PC 02和pH。通过外周神经系统发生对解释性控制中心的感觉反馈。 和中央化学感受器，但有几个悬而未决的问题，有关的机制， 被认为充当中心CO2/pH化学感受器的神经元的特定亚群的相对重要性。 是什么赋予了选择神经元“感知”pH值的内在能力？信号传导有哪些 pH的路径？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 觉醒）？本提案的总体目标是解决其中一些有关中央 通过利用独特的近交系大鼠品系的化学感受性，所述近交系大鼠品系在CO2中具有固有的和大的差异 敏感性; Brown Nonway（BN：低响应）和Dahl盐敏感性（SS：高响应）大鼠。第一、 我们将确定BN大鼠中CO2敏感性的缺陷是否是由于细胞CO2/pH敏感性的降低， 在体外培养单个化学敏感神经元，这将有助于转基因大鼠的发展 在选择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中产生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， 脑干中的神经调质可能有助于BN大鼠中的CO2敏感性减弱，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CO2 BN大鼠的敏感性。从这些独特的大鼠品系中获得的数据将为以下方面提供重要的见解： 特异性化学感受器亚群调节正常呼吸的机制及其相对重要性 通气和呼吸CO2敏感性。它们还将提供对与生殖器有关的疾病的见解， 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， 中枢化学感受发生的独特细胞机制。

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.