Transmitters in Altered Carotid Body Function

描述（由申请人提供）：人类由于复发性呼吸暂停而经历慢性间歇性缺氧（CIH），并发展为自主神经疾病。已经提出颈动脉化学感受器触发CIH诱导的心肺功能异常。我们的研究表明，CIH诱导持久的化学感受器激活（即，感觉长时程易化（LTF），这又可能触发交感神经紧张的反射增加，以及高血压。目前的建议的目标是确定与CIH诱导的感觉LTF相关的机制，并评估感觉LTF在诱发自主神经异常中的意义。我们假设感觉LTF是由于CIH招募某些递质/调节剂，否则在正常颈动脉体功能中起次要作用或不起作用。具体而言，5-羟色胺（5-HT）和随后的激活NADPH氧化酶在CIH诱导的感觉LTF的作用将被检查。实验将在大鼠和基因工程小鼠上进行。将采用包括颈动脉体感觉活动、心肺变量、神经递质和第二信使通路测量在内的一系列技术的综合方法。AIM 1中的实验检验了缺氧暴露方案的频率在确定CIH诱发的感觉LTF的幅度中起重要作用的假设。AIM 2中的研究检验了以下假设：A）通过5-HT 2受体起作用的5- HT在CIH诱发的感觉LTF中起关键作用，和B）CIH在诱发5-HT从颈动脉体释放中募集IP-3受体机制。AIM 3中的方案测试了CIH诱发的感觉LTF需要通过5-HT 2受体激活NADPH氧化酶并随后产生O2的假设。在颈动脉体。AIM 4中的实验检验了以下假设：阻断颈动脉体中的5-HT和NADPH氧化酶减弱或消除CIH诱发的长期心脏-呼吸变化。所提出的评估递质在CIH诱导的颈动脉体感觉LTF中的作用以及评估感觉LTF的生理学意义的研究对于开发用于减轻和/或延缓与CIH相关的自主神经异常的新的治疗策略具有重要意义。 公共卫生相关性：导致复发性呼吸暂停的睡眠呼吸障碍是美国人群发病率和死亡率的主要原因。该领域的主要进展是确定慢性间歇性缺氧（CIH）是与呼吸暂停相关的心肺疾病的主要原因。颈动脉体是检测动脉血氧的主要感觉器官，介导CIH引起的发病率。目前的建议是研究神经递质在实验模型中CIH改变颈动脉体功能中的作用，这可能会导致新的治疗策略，有助于预防或延缓与睡眠呼吸障碍相关的CIH的有害后果。

DESCRIPTION (provided by applicant): Humans experience chronic intermittent hypoxia (CIH) as a consequence of recurrent apneas and develop autonomic morbidity. It has been proposed that carotid chemoreceptors trigger CIH-induced cardio-respiratory abnormalities. Our studies showed that CIH induces long lasting chemoreceptor activation (i.e., sensory long-term facilitation LTF), which in turn may trigger reflex increase in sympathetic tone, and hypertension. The goal of the current proposal is to identify the mechanisms associated with CIH-induced sensory LTF and assess the significance of sensory LTF in evoking autonomic abnormalities. We hypothesize that sensory LTF is due to recruitment of certain transmitter/modulators by CIH, which otherwise play either a minor or no role in normal carotid body function. Specifically, the role of 5-hydroxytryptamine (5-HT) and subsequent activation of NADPH oxidase in CIH-induced sensory LTF will be examined. Experiments will be performed on rats as well as genetically engineered mice. An integrated approach with a repertoire of techniques including measurements of carotid body sensory activity, cardio-respiratory variables, neurotransmitters and second messenger pathways will be employed. Experiments in AIM 1 test the hypothesis that frequency of the hypoxic exposure regimen plays an important role in determining the magnitude of CIH-evoked sensory LTF. Studies in AIM 2 test the hypotheses that: A) 5- HT acting via 5-HT2 receptors plays a critical role in CIH evoked sensory LTF and b) CIH recruits IP-3 receptor mechanisms in eliciting 5-HT release from the carotid body. Protocols in AIM 3 test the hypothesis that CIH-evoked sensory LTF requires activation of NADPH oxidase by 5-HT2 receptors and subsequent generation of O2.- in the carotid body. Experiments in AIM 4 test the hypothesis that blockade of 5-HT and NADPH oxidase in the carotid body attenuate or abolish CIH-evoked long-lasting cardio- respiratory changes. The proposed studies assessing the role of transmitter(s) in CIH- induced sensory LTF of the carotid body and assessing the physiological significance of sensory LTF is of importance in developing novel therapeutic strategies for alleviating and/or retarding autonomic abnormalities associated with CIH. PUBLIC HEALTH RELEVANCE: Sleep disordered breathing leading to recurrent apneas is a major cause of morbidity and mortality in U.S. population. Major advance in the field is the identification that chronic intermittent hypoxia (CIH) is the major contributor to the cardio-respiratory morbidity associated with apneas. Carotid bodies, the principal sensory organs for detecting arterial blood oxygen, mediate CIH-induced morbidity. The current proposal proposes to investigate the role of neurotransmitters in altered carotid body function by CIH in experimental models that may lead to novel therapeutic strategies that help in preventing or retarding the deleterious consequences of CIH associated with sleep-disordered breathing.