Determining the mechanisms underlying a potential treatment for sleep apnea

确定潜在治疗睡眠呼吸暂停的机制

• 批准号: 7962973
• 负责人: WALTER E BABIEC
• 金额: $ 1.04万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7962973
• 关键词: AMPA Receptors; Action Potentials; Adult; Affect; Aging; Airway Resistance; Altitude; American; Anesthesia procedures; Antihypertensive Agents; Bathing; Behavior; Blood Pressure; Breathing; Carbon Dioxide; Cell Nucleus; Cell Respiration; Chemoreceptors; Corpus striatum structure; Data; Development; Disease; Diuretics; Dose; Effectiveness; Exercise; Failure; Fostering; Functional disorder; Generations; Glutamate Receptor; Health; Heart Rate; Hippocampus (Brain); Hour; Human; Hypoglossal nerve structure; In Vitro; Injection of therapeutic agent; Isoflurane; Long-Term Effects; Lung; Mammals; Mastication; Mentors; Methods; Modeling; Motor; Motor Neurons; Motor output; Movement; Muscle; Muscle Contraction; Neonatal; Nerve; Neurons; Obstructive Sleep Apnea; Opiates; Overdose; Paralysed; Pattern; Peripheral; Pharmaceutical Preparations; Pharmacological Treatment; Physiological Processes; Plant Roots; Preparation; Production; Property; Rattus; Respiratory Muscles; Severities; Signal Transduction; Site; Sleep Apnea Syndromes; Sleep Wake Cycle; Slice; Spinal cord injury; Synapses; Synaptic plasticity; Testing; Time; Tongue; Ventilatory Depression; base; cyclothiazide; desensitization; improved; interest; neuroregulation; preBotzinger complex; prevent; receptor recycling; respiratory; response; voltage

DESCRIPTION (provided by applicant): A profound and long-lasting facilitation of endogenously-generated, respiratory- related hypoglossal nerve activity in the neonatal rat medullary slice preparation has been discovered. It results from a 1-hour bath application of the AMPA receptor anti-desensitization drug cyclothiazide (CTZ). This phenomenon, termed CTZ-induced facilitation (CIF), consistently lasts >12 hours following the completion of drug application but does not depend upon activation of ionotropic glutamate receptors during administration of CTZ. This facilitation of hypoglossal nerve activity is triple that seen in another model of respiratory plasticity studied in this lab, in vitro long-term facilitation (ivLTF). Importantly, these observations are behaviorally relevant. Injection of CTZ into intact, isoflurane-anesthetized, adult rats facilitates the amplitude of phasic genioglossus (GG) muscle activity without affecting respiratory rate or heart rate. The mechanism underlying CIF is unknown. This project will test 3 mechanisms that, based on preliminary data, most likely underlie CIF, after characterizing the dynamics and intracellular effects of this phenomenon in greater detail. Aim 1 has two objectives: (i) determine whether the duration of CTZ application along with CTZ concentration determines the magnitude and time course of CIF; (ii) parse the effects of CTZ on the respiratory control circuit by focally applying CTZ to 3 regions in the slice known to affect respiratory rhythm. Aim 2 investigates how CTZ exposure modifies fast excitatory signaling, inhibitory signaling, and firing properties within hypoglossal motoneurons in the short and long terms, establishing a baseline intracellular response for testing the mechanisms hypothesized to underlie CIF. Aim 3 tests the mechanisms hypothesized to underlie CIF: (i) permanent abolition of AMPA receptor desensitization, (ii) direct intracellular action, (iii) disruption of constitutive AMPA receptor recycling. RELEVANCE: Obstructive sleep apnea (OSA) is a disease that affects as many as 1 in 5 adult Americans in varying degrees of severity. Currently, there is no pharmacological treatment for this disease; while, other methods of treatment are highly invasive and/or of limited effectiveness. An understanding of the mechanisms underlying facilitation of respiratory motor output to muscles of the tongue and upper airway will foster the development of effective, easy to use treatments improving the long-term health of millions.

描述（由申请人提供）：已发现在新生大鼠髓质切片制剂中对内源性呼吸相关舌下神经活动具有深远且持久的促进作用。这是由于使用 AMPA 受体抗脱敏药物环噻嗪 (CTZ) 沐浴 1 小时而产生的。这种现象被称为 CTZ 诱导促进 (CIF)，在药物应用完成后始终持续 > 12 小时，但不依赖于 CTZ 给药期间离子型谷氨酸受体的激活。这种舌下神经活动的促进作用是本实验室研究的另一种呼吸可塑性模型（体外长期促进作用（ivLTF））中观察到的三倍。重要的是，这些观察结果与行为相关。将 CTZ 注射到完整的、异氟烷麻醉的成年大鼠中，可促进阶段性颏舌肌 (GG) 肌肉活动的幅度，而不影响呼吸频率或心率。 CIF 的潜在机制尚不清楚。该项目将测试 3 种机制，根据初步数据，在更详细地描述这种现象的动力学和细胞内效应后，这些机制很可能是 CIF 的基础。目标 1 有两个目标：(i) 确定 CTZ 应用的持续时间以及 CTZ 浓度是否决定了 CIF 的幅度和时间进程； (ii) 通过将 CTZ 集中应用到切片中已知影响呼吸节律的 3 个区域来解析 CTZ 对呼吸控制回路的影响。目标 2 研究 CTZ 暴露如何在短期和长期内改变舌下运动神经元内的快速兴奋信号、抑制信号和放电特性，建立基线细胞内反应来测试假设的 CIF 机制。目标 3 测试 CIF 的假设机制：(i) 永久消除 AMPA 受体脱敏，(ii) 直接细胞内作用，(iii) 破坏 AMPA 受体的组成型再循环。相关性：阻塞性睡眠呼吸暂停 (OSA) 是一种影响多达五分之一的美国成年人的疾病，其严重程度各不相同。目前，这种疾病没有药物治疗方法；而其他治疗方法具有高度侵入性和/或效果有限。了解促进舌头和上呼吸道肌肉呼吸运动输出的机制将有助于开发有效、易于使用的治疗方法，从而改善数百万人的长期健康。