Roles of peripheral and central respiratory chemoreceptors in inbred rat strains

描述(由申请人提供)：换气的剧烈调整代表了维持P02、PC02和pH的强大的动态平衡机制。感觉反馈到呼吸控制中心是通过外周和中枢化学感受器实现的，但关于中枢性化学感受器的作用和相对重要性，以及它们在常压通气过程中对血气调节的贡献，以及外周化学感受器和中枢化学感受器之间的可能相互作用，仍有几个悬而未决的问题。这项提案的总体目标是通过利用独特的近交系大鼠品系来解决有关化学接收的问题，这些品系具有固有的和巨大的二氧化碳敏感性差异；棕色挪威鼠(BN：低响应者)和Dahl盐敏感鼠(SS：高响应者)。首先，我将确定BN大鼠二氧化碳敏感性的下降是由于单个体外化疗敏感神经元对二氧化碳/pH敏感性的降低，还是由于免疫组织化学方法检测到化疗敏感神经元的数量和/或形态发生了变化。第二个目标将通过表征颈动脉体失神经对这些品系的影响来检验中枢化学感受器在常压PC02和pH调节中作用不大的假设。最后，有证据表明颈动脉化学感受器可能直接调节中枢二氧化碳敏感性。在第三个目标中，我将使用体内和体外相结合的方法来测试这种可能性，首先测量对焦点的换气反应。 成年BN和SS大鼠化疗敏感区酸中毒及细胞CO_2/pH定量 BN和SS新生儿培养前后单个中枢化学感受器神经元的体外敏感性 颈动脉体失神经。将这些实验技术应用于这些独特的大鼠品系，将为深入了解外周和中枢化学感受在常压通风中的相对作用和重要性，以及它们可能的相互作用提供重要的见解。它们还将提供对与呼吸相关的疾病的洞察，并将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，从而确定发生中央化学接收的独特细胞机制。

DESCRIPTION (provided by applicant): Acute adjustments in ventilation represent a powerful homeostatic mechanism for the maintenance of P02, PC02 and pH. Sensory feedback to the ventilatory control centers occurs via peripheral and central chemoreceptors, but here are several unresolved questions regarding the roles and relative importance of central chemoreceptors and their contributions to blood gas regulation during eupneic ventilation, and putative interactions peripheral chemoreceptors and central chemoreceptors. The overall goal of this proposal are to address questions regarding chemoreception by taking advantage of unique inbred rat strains with inherent, and large differences in C02 sensitivity; the Brown Norway (BN: low responder) and Dahl Salt-sensitive (SS: high responder) rat. First, I 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, or numbers and/or altered morphology of chemosensitive neurons via immunohistochemistry. The hypothesis that central chemoreceptors play little role .in the regulation of eupneic PC02 and pH will be tested in the second aim by characterizing the effects of carotid body denervation in these strains. Last, there is evidence that the carotid chemoreceptors may directly regulate central C02 sensitivity. In the third aim, I will test this possibility using a combined in vivo and in vitro approach by first measuring the ventilatory response to focal acidosis in chemosensitive regions in adult BN and SS rats, and then by quantifying the cellular C02/pH sensitivity of individual central chemoreceptor neurons in vitro in BN and SS neonates before and after carotid body denervation. Applying these experimental techniques to these unique rat strains will provide significant insights into the relative roles and importance of peripheral and central chemoreception in eupneic ventilation, and their putative interaction. They will also provide insights into respiratory-related diseases, and will provide a framework for future genomic investigations aimed at identifying the genetic determinants, and therefore the unique cellular mechanisms by which central chemoreception occurs.