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）：已经发现了内源性生成的，与新生大鼠髓质切片制剂中内源性，呼吸相关的降低神经活性的深刻而持久的促进。它是由AMPA受体抗脱敏化药物cyclothiazide（CTZ）的1小时浴造成的。这种现象称为CTZ诱导的促进作用（CIF），在施用药物后始终持续> 12小时，但不依赖于在CTZ给药过程中激活离子型谷氨酸受体。这种促脑神经活性的促进是三倍，在该实验室中研究的另一种呼吸可塑性模型中，体外长期促进（IVLTF）。重要的是，这些观察在行为上是相关的。将CTZ注入完整，异氟烷 - 麻醉的成年大鼠，促进了阶段性Genioglossus（GG）肌肉活性的幅度，而不会影响呼吸率或心脏速度。 CIF的基础机制尚不清楚。该项目将测试三种机制，这些机制基于初步数据，最有可能是CIF的基础，此前将这种现象的动力学和细胞内效应更详细地表征。 AIM 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CIF的幅度和时间过程； （ii）通过将CTZ局部应用于已知影响呼吸节奏的切片中的3个区域，解析CTZ对呼吸控制回路的影响。 AIM 2研究了CTZ暴露如何在短期和长期内修改降压运动神经元内的快速兴奋性信号传导，抑制信号传导和发射特性，从而建立了基线内响应，以测试假设在CIF基础的机制。 AIM 3测试CIF构成的机制：（i）永久废除AMPA受体脱敏，（ii）直接细胞内作用，（iii）构成型AMPA受体回收的破坏。相关性：阻塞性睡眠呼吸暂停（OSA）是一种疾病，其严重程度不同，多达5名成年美国人中有1个。目前，该疾病尚无药理治疗。而其他治疗方法具有高度侵入性和/或有限的有效性。对呼吸运动输出促进的机制的理解将促进舌头和上呼吸道的肌肉，从而促进有效的，易于使用的治疗方法的发展，改善了数百万的长期健康状况。