Roles of peripheral and central respiratory chemoreceptors in inbred rat strains

描述（由申请人提供）：通气的急性调节是维持P02、PC02和ph的一种强大的内稳态机制。通过外周和中枢化学感受器向通气控制中心进行感觉反馈，但关于中枢化学感受器的作用和相对重要性及其在缺氧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可能的相互作用，还有几个尚未解决的问题。本提案的总体目标是通过利用独特的近亲繁殖的大鼠菌株来解决有关化学接受的问题，这些大鼠菌株在二氧化碳敏感性方面具有固有的和巨大的差异；褐挪威（BN：低反应）和达尔盐敏感（SS：高反应）大鼠。首先，我将确定BN大鼠的二氧化碳敏感性缺陷是由于体外单个化学敏感神经元的细胞二氧化碳/pH敏感性降低，还是由于免疫组织化学的化学敏感神经元的数量和/或形态改变。中枢化学感受器作用不大的假说。将在第二个目标中通过表征颈动脉体去神经支配在这些菌株中的作用来测试血浆PC02和pH的调节。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，我将通过首先测量对焦点的通气反应，使用体内和体外结合的方法来测试这种可能性

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.