Roles of peripheral and central respiratory chemoreceptors in inbred rat strains

描述（申请人提供）：通气的急性调节代表了用于维持P02、PC 02和pH的强大的稳态机制。通过外周和中枢化学感受器发生对呼吸控制中心的感觉反馈，但是关于中枢化学感受器的作用和相对重要性以及它们在正常通气期间对血气调节的贡献，存在几个未解决的问题。以及外周化学感受器和中枢化学感受器的假定相互作用。该提议的总体目标是通过利用具有固有的和大的CO2敏感性差异的独特的近交系大鼠品系来解决关于化学感受的问题; Brown Norway（BN：低响应者）和Dahl盐敏感性（SS：高响应者）大鼠。首先，我将通过免疫组织化学确定BN大鼠中CO2敏感性的缺陷是否是由于体外单个化学敏感性神经元的细胞CO2/pH敏感性降低，或化学敏感性神经元的数量和/或形态改变。在第二个目标中，将通过表征这些菌株中颈动脉体去神经支配的影响来测试中枢化学感受器在正常呼吸PC 02和pH调节中几乎没有作用的假设。最后，有证据表明颈动脉化学感受器可以直接调节中枢CO2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，首先测量对局灶性 在成年BN和SS大鼠中化学敏感区域的酸中毒，然后通过定量细胞CO2/pH BN和SS新生儿中单个中枢化学感受器神经元在体外的敏感性 颈动脉体去神经将这些实验技术应用于这些独特的大鼠品系，将提供显着的见解外周和中枢化学感受在正常通气的相对作用和重要性，以及它们之间的相互作用。他们还将提供洞察力相关的疾病，并将提供一个框架，为未来的基因组研究，旨在确定遗传决定因素，因此，独特的细胞机制，中央化学感受发生。

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.