Signal Transduction in Intrapulmonary Chemoreceptors

描述（由申请人提供）：我们将研究鸟类肺内化学感受器（IPC）中二氧化碳转导的细胞机制，作为脊椎动物呼吸二氧化碳转导的一般原理的模型。我们将利用这项研究向北亚利桑那大学的本科生和研究生介绍生物医学研究，通过实践实验经验和科学实践培训。本文的目的一是测试v型H+ atp酶和H+/K+- atp酶的质子主动转运是否参与IPC的pH调节和CO2转导。康诺霉素A和埃索美拉唑将被使用，同时记录单个化学受体对阶段性二氧化碳刺激的反应。Aim II将测试瞬时乳酸积累或KATP通道是否在IPC尖峰频率适应（SFA）中发挥作用，使用乳酸输注和格列本脲进行单单位记录。Aim III将验证IPC共享哺乳动物二氧化碳敏感肺拉伸受体（PSR）中发现的一些信号转导特性的假设，这将表明PSR和IPC之间存在一定程度的系统发育同源性。4-氨基吡啶是一种快速K+离子通道阻滞剂，可降低PSR对CO2的反应；氯化钆是一种拉伸激活离子通道阻滞剂，可损害PSR对肺部膨胀的反应，将在单单元IPC中进行研究。目的IV将研究Na+/K+ atp酶在激活IPC膜和通过Na+/Ca++交换影响Ca++水平中的作用。这项研究将增强对呼吸化学感受器的理解，吸引和培养NAU未来的科学家，并可能为治疗二氧化碳化学敏感性疾病提供有用的医学治疗方法。

DESCRIPTION (provided by applicant): We will study the cellular mechanisms of CO2 transduction in avian intrapulmonary chemoreceptors (IPC) as a model for general principles of respiratory CO2 transduction in vertebrates. We will use this research to introduce undergraduate and graduate students at Northern Arizona University to biomedical research using hands-on lab experiences and training in scientific practice. Aim I of this proposal will test whether active proton transport by v-type H+ ATPase and H+/K+-ATPase participate in pH regulation and CO2 transduction in IPC. Concanomycin A and esomeprazole will be used while recording single unit chemoreceptor responses to phasic CO2 stimuli. Aim II will test whether transient lactic acid accumulation or KATP channels play roles in IPC spike frequency adaptation (SFA), using lactate infusion and glibenclamide with single-unit recordings. Aim III will test the hypothesis that IPC share some signal transduction properties found in mammalian CO2-sensitive pulmonary stretch receptors (PSR), which would indicate a degree of phylogenetic homology between PSR and IPC. 4-amino pyridine, a fast K+ ion channel blocker shown to decrease PSR response to CO2, and gadolinium chloride, a blocker of stretch activated ion channels which impairs PSR response to lung inflation, will be studied in single-unit IPC. Aim IV will investigate the role of Na+/K+ ATPase in energizing the IPC membrane and influencing Ca++ levels via Na+/Ca++ exchange. This research will enhance understanding of respiratory chemoreceptors in general, attract and train of future scientists at NAU, and may suggest medical treatments useful for treating disorders in CO2 chemosensitivity. PUBLIC HEALTH RELEVANCE: This research investigates fundamental neural processes that detect CO2 levels in the body and send neural signals to the brain that control breathing. This is important for human health, because better understanding of respiratory CO2 chemotransduction may help develop more effective treatments and drugs for the loss of CO2 chemosensitivity, a common complication seen in patients with severe cardiopulmonary disease. The research will also be used to stimulate interest and give hands-on scientific experience to undergraduate and graduate students at Northern Arizona University interested in biomedical research careers.