Neurotransmitter Metabolism in Intermittent Hypoxia

间歇性缺氧中的神经递质代谢

• 批准号: 8050610
• 负责人: Ganesh K Kumar
• 金额: $ 38.38万
• 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: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8050610
• 关键词: Abbreviations; Acute; Adrenal Cortex; Adrenal Glands; Adrenal Medulla; Adrenalectomy; Adult; Affect; Animals; Apnea; Attenuated; Biological; Blood; Blood Pressure; Calcium; Calcium Channel; Calcium Signaling; Cardiovascular Abnormalities; Cardiovascular system; Catecholamines; Chronic; Continuous Positive Airway Pressure; Coupled; Data; Detection; Development; Enzyme Immunoassay; Epinephrine; Evaluation; GTP-Binding Proteins; Generations; Genetic; Glycine; Goals; Health; High Pressure Liquid Chromatography; Hormones; Human; Hypertension; Hypoxia; Knockout Mice; Literature; Mediating; Messenger RNA; Methods; Mixed Function Oxygenases; Monitor; Morbidity - disease rate; Mus; Nerve; Neuropeptide Y Receptor; Norepinephrine; Obstructive Sleep Apnea; Patients; Peptides; Peripheral; Plasma; Play; Population; Process; Proteolytic Processing; Rattus; Reactive Oxygen Species; Reagent; Recruitment Activity; Recurrence; Reporting; Research Design; Risk; Role; SHFM1 gene; Signal Transduction; Sleep Apnea Syndromes; Slice; Stimulus; Sympathetic Nervous System; Testing; United States; Wild Type Mouse; amidation; awake; base; design; effective intervention; experience; in vivo; inhibitor/antagonist; insight; mortality; neuropeptide Y; neurotransmitter metabolism; new therapeutic target; peptidylglycine alpha-amidating monooxygenase; prevent; receptor; research study; respiratory; response; voltage

DESCRIPTION (provided by applicant): Humans, experiencing chronic intermittent hypoxia (CIH), are prone to develop hypertension. Previous studies showed that rats and mice exposed to CIH have increased blood pressure, elevated circulating catecholamines (CA) and increased levels of vasoactive substances including norepinephrine and neuropeptide Y (NPY) in the adrenal medulla. To begin to define the mechanism(s) by which CIH evokes cardiovascular changes, we propose to test the following interlinked hypotheses: i) CIH facilitates the synthesis and stimulus-evoked release of NPY; ii) Exogenously released NPY, in turn, via activation of NPY receptor subtypes and the downstream G-protein mediated signaling cascade contributes to CIH-induced increases in CA release, and iii) CIH-evoked functional interaction between NPY and CA in the sympathetic nervous system contributes to cardiovascular changes elicited by CIH. These hypotheses will be tested in the adrenal medulla of rats exposed to CIH. In Aim 1, the effects of CIH on the synthesis of bioactive NPY both at the mRNA (preproNPY) and at the peptide levels and the potential contribution of peptidylglycine a-amidating monooxygenase (PAM) in CIH-induced alterations in NPY levels will be assessed. In Aim 2, the effects of CIH on stimulus-evoked NPY release and the role of cytosolic calcium in eliciting this response will be determined. Studies in Aim 3 will examine the critical role(s) of NPY Y receptors (Y1 and Y2) and G-protein mediated cell signaling in CIH-induced facilitation of CA release by hypoxia. To delineate the potential contribution of NPY receptor subtypes, the effects of NPY receptor subtype specific antagonists and targeted deletion of NPY receptor subtypes on CIH-evoked changes in CA release will be assessed. Studies in Aim 4 are designed to assess the direct and/or indirect contributions of NPY and its receptor subtypes and PAM to CIH-evoked cardiovascular changes in unanesthetized, awake animals. It is anticipated that the proposed studies will provide new mechanistic insights into CIH-evoked functional alterations in the peripheral sympathetic nervous system and aid in the identification of novel therapeutic targets for effective intervention of cardiovascular abnormalities associated with recurrent apneas. PUBLIC HEALTH RELEVANCE. Sleep-disordered breathing with recurrent apneas is a major cause of morbidity and mortality in the United States population, affecting an estimated 18 million people. Patients with chronic intermittent hypoxia (CIH) caused by sleep apnea have a greatly increased risk for the development of systemic hypertension. The mechanism(s) by which CIH associated with recurrent apneas are initiated leading to cardio-respiratory morbidity, however, are not fully understood. The proposal aims to elucidate the role of functional interactions between two potent vasoactive substances such as neuropeptide Y and catecholamines in the peripheral sympathetic nervous system in CIH-evoked elevation in blood pressure. These studies are expected to provide new therapeutic targets for alleviating the cardiovascular morbidity associated with recurrent apneas.

描述（由申请人提供）：经历慢性间歇性缺氧（CIH）的人类容易患高血压。先前的研究表明，暴露于 CIH 的大鼠和小鼠血压升高，循环儿茶酚胺 (CA) 升高，肾上腺髓质中包括去甲肾上腺素和神经肽 Y (NPY) 在内的血管活性物质水平升高。为了开始定义 CIH 引起心血管变化的机制，我们建议测试以下相互关联的假设： i) CIH 促进 NPY 的合成和刺激诱发的释放； ii) 反过来，通过激活 NPY 受体亚型和下游 G 蛋白介导的信号级联，外源释放的 NPY 有助于 CIH 诱导的 CA 释放增加，以及 iii) CIH 诱发交感神经中 NPY 和 CA 之间的功能相互作用系统有助于 CIH 引起的心血管变化。这些假设将在暴露于 CIH 的大鼠的肾上腺髓质中进行测试。在目标 1 中，将评估 CIH 对 mRNA (preproNPY) 和肽水平上生物活性 NPY 合成的影响，以及肽基甘氨酸 α-酰胺化单加氧酶 (PAM) 在 CIH 诱导的 NPY 水平变化中的潜在贡献。在目标 2 中，将确定 CIH 对刺激诱发的 NPY 释放的影响以及胞质钙在引发这种反应中的作用。目标 3 的研究将检验 NPY Y 受体（Y1 和 Y2）和 G 蛋白介导的细胞信号传导在 CIH 诱导的缺氧促进 CA 释放中的关键作用。为了描述 NPY 受体亚型的潜在贡献，将评估 NPY 受体亚型特异性拮抗剂和 NPY 受体亚型的靶向删除对 CIH 诱发的 CA 释放变化的影响。目标 4 中的研究旨在评估 NPY 及其受体亚型和 PAM 对未麻醉、清醒动物中 CIH 诱发的心血管变化的直接和/或间接贡献。预计拟议的研究将为 CIH 引起的周围交感神经系统功能改变提供新的机制见解，并有助于确定新的治疗靶点，以有效干预与反复呼吸暂停相关的心血管异常。公共卫生相关性。睡眠呼吸障碍伴反复呼吸暂停是美国人口发病和死亡的主要原因，估计影响了 1800 万人。由睡眠呼吸暂停引起的慢性间歇性缺氧（CIH）患者发生全身性高血压的风险大大增加。然而，与反复性呼吸暂停相关的 CIH 引发导致心肺疾病的机制尚不完全清楚。该提案旨在阐明周围交感神经系统中两种强效血管活性物质（例如神经肽 Y 和儿茶酚胺）之间的功能相互作用在 CIH 引起的血压升高中的作用。这些研究有望为减轻与反复呼吸暂停相关的心血管发病率提供新的治疗靶点。