Transmitters in Altered Carotid Body Function

改变颈动脉体功能的递质

• 批准号: 7884488
• 负责人: Nanduri R Prabhakar
• 金额: $ 35.1万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-26 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884488
• 关键词: Adult; Apnea; Attenuated; Biochemical; Blood; Blood Pressure; Breathing; CNS processing; Carbon Dioxide; Carotid Body; Chemoreceptors; Chronic; Complex; Data; Experimental Models; Frequencies; Generations; Genetic; Genetically Engineered Mouse; Goals; Human; Hypertension; Hypoxia; In Vitro; Lead; Measurement; Mediating; Minor; Monitor; Morbidity - disease rate; Mus; NADPH Oxidase; Nerve; Neurotransmitters; Organ; Oxidases; Oxygen; Oxygen measurement, partial pressure, arterial; Pathway interactions; Physiological; Play; Population; Protocols documentation; Rattus; Receptor Activation; Recruitment Activity; Recurrence; Reflex action; Regimen; Rodent; Role; Second Messenger Systems; Sensory; Serotonin; Signal Transduction; Sleep Apnea Syndromes; Structure of phrenic nerve; Techniques; Testing; afferent nerve; base; conditioning; experience; in vivo; inhibitor/antagonist; mortality; novel; novel therapeutics; prevent; public health relevance; receptor; research study; respiratory; response; second messenger

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.

描述（由申请人提供）：人类由于经常性呼吸暂停而经历慢性间歇性缺氧（CIH）并发展自主性发病率。已经提出，颈动脉化学感受器会触发CIH诱导的心呼吸异常。我们的研究表明，CIH诱导了持久的化学感受器激活（即感觉长期促进LTF），这又可能触发交感神经反射和高血压的反射增加。当前建议的目的是确定与CIH诱导的感觉LTF相关的机制，并评估感觉LTF在唤起自主神经异常中的重要性。我们假设感觉LTF是由于CIH募集了某些发射器/调节剂，否则这些发射器/调节剂在正常的颈动脉体功能中扮演次要或无角色。具体而言，将检查5-羟色胺（5-HT）和随后的NADPH氧化酶在CIH诱导的感觉LTF中的作用。实验将对大鼠以及基因工程小鼠进行。将采用一系列技术的综合方法，包括测量颈动脉身体感觉活动，心脏响应变量，神经递质和第二层信使途径。 AIM 1中的实验检验了以下假设：低氧暴露方案的频率在确定CIH诱发的感觉LTF的幅度中起着重要作用。 AIM 2的研究检验了：a）5-HT通过5-HT2受体作用在CIH引起的感觉LTF和B）CIH募集IP-3受体机制在从Carotid体中引发5-HT释放的IP-3受体机制起着至关重要的作用。 AIM 3中的方案检验了CIH诱发的感觉LTF的假设需要通过5-HT2受体激活NADPH氧化酶，然后在颈动脉体内激活O2。 AIM 4中的实验检验了以下假设：颈动脉体中的5-HT和NADPH氧化酶的阻断衰减或废除了CIH引起的长期持久的心脏呼吸变化。提出的研究评估发射机在颈动脉体内CIH诱导的感觉LTF中的作用并评估感觉LTF的生理意义对于制定新的治疗策略以减轻和/或与CIH相关的自治异常。 公共卫生相关性：睡眠障碍呼吸导致反复发生的呼吸暂停是美国人群发病率和死亡率的主要原因。该领域的主要进步是鉴定，慢性间歇性缺氧（CIH）是导致与呼吸暂停相关的心脏呼吸性发病率的主要因素。颈动脉体是用于检测动脉血氧的主要感觉器官，可介导CIH引起的发病率。当前的建议建议在实验模型中研究神经递质在改变颈动脉身体功能中的作用，这些模型可能导致新的治疗策略，有助于预防或阻碍与睡眠分离的呼吸相关的CIH的有害后果。