Obstructive Sleep Apnea - An Obese Minipig Model

阻塞性睡眠呼吸暂停 - 肥胖小型猪模型

• 批准号: 9032978
• 负责人: Zijun Liu
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9032978
• 关键词: Academy; Address; Adipose tissue; Adult; Adverse effects; American; Anatomy; Animal Model; Animals; Anterior; Back; Clinical Data; Clinical Treatment; Constitution; Craniofacial Abnormalities; Deposition; Development; Electrocardiogram; Electroencephalography; Electromyography; Evaluation; Family suidae; Fatty acid glycerol esters; Fiber; Functional disorder; Histologic; Human; Implant; Infiltration; Knowledge; Larynx; Letters; Liquid substance; Longitudinal Studies; Magnetic Resonance Elastography; Magnetic Resonance Imaging; Measurement; Mechanics; Medicine; Miniature Swine; Modality; Modeling; Morphology; Muscle; Non obese; Obesity; Obstructive Sleep Apnea; Operative Surgical Procedures; Oropharyngeal; Outcome; Pathogenesis; Patients; Physiological; Polysomnography; Positioning Attribute; Research; Resistance; Respiration; Respiration Disorders; Risk Factors; Role; Shapes; Site; Sleep; Snoring; Soft Palate; Solid; Structure; Technology; Testing; Therapeutic Intervention; Tissues; Validation; Weight; human study; in vivo; instrumentation; meetings; muscular structure; neuromuscular; neuromuscular stimulation; public health relevance; simulation; sleep position; tongue root; tool

 DESCRIPTION (provided by applicant): The tongue base and soft palate constitute the anterior border of oropharynx and control the entrance into the larynx. Thus, their size, position, and mobility have a crucial influence on the upper airway (UA). Clinical data show that patients with obstructive sleep apnea or hypopnea (OSA) commonly have anatomic compromise of the UA due to either excessive tissue mass or neuromuscular compromise of the tongue base and/or soft palate. However, information about how shape and mobility of the tongue base and soft palate contribute to the UA collapse during sleep is very limited. Human study cannot address these critical questions underlying the pathogenesis and pathophysiology of OSA because of the invasive technology necessary. Thus, a suitable and reliable animal model is an imperative. This model must meet three basic criteria: 1) anatomical and functional similarity to humans; 2) presentation of spontaneous OSA with UA collapse; and 3) an appropriate size for physiological instrumentation and therapeutic interventions. Pigs have considerable similarity with humans in UA constitution and function, and spontaneous OSA occurs in obese minipigs. The obese minipig is especially appropriate because excess weight and obesity is the strongest risk factor for the development of OSA and an independent predictor of OSA in humans. This promising model has not yet been evaluated for UA collapse in OSA. Establishment of a validated large animal model would be foundational to our understanding of vital function and morphology of the tongue base and soft palate in respiration, would facilitate refinement of clinical treatment for breathing disorders, would allow study of the longitudinal consequences of mechanical and surgical treatment modalities, and would enable evaluation of controversial therapies such as neuromuscular stimulation and pharmacological application under well-controlled experimental conditions. Therefore, we propose this exploratory study to establish an obese minipig model for use in OSA research, and to determine the roles of the tongue base, soft palate, and pharyngeal wall in UA function and collapse during sleep. We will first validate OSA in obese minipigs, verify OSA absence in controls, and identify the obstructive site(s) in OSA to test the hypothesis that obese minipigs present spontaneous OSA with UA collapse, and non-obese controls have no sign of OSA (Aim 1). Using these validated OSA animals, we will determine the physical mechanism whereby obesity leads to UA collapse by comparing morphology and mobility of the tongue base and soft palate in controls and obese minipigs with OSA to test the hypothesis that compared to controls, obese OSA minipigs present excessive mass and stiffness, reduced mobility, and greater fat infiltration in the tongue base, soft palate, and pharyngeal wall, which in turn compress the UA and increase its resistance for respiration during sleep (Aim 2). The outcomes will establish a suitable and reliable animal model with well-characterized UA morphology and function to facilitate OSA studies in various fields.

 描述（由申请人提供）：舌根和软腭构成口咽的前缘，并控制进入喉的入口。因此，它们的大小，位置， 和流动性对上气道（UA）有至关重要的影响。临床资料显示，阻塞性睡眠呼吸暂停或低通气（OSA）患者通常由于舌根和/或软腭的过度组织质量或神经肌肉损害而导致UA的解剖损害。然而，关于舌根和软腭的形状和流动性如何在睡眠期间促成UA塌陷的信息非常有限。人类研究不能解决这些关键问题的发病机制和病理生理学的OSA，因为侵入性技术的必要。因此，一个合适的和可靠的动物模型是必要的。该模型必须满足三个基本标准：1）解剖和功能与人类相似; 2）自发性OSA伴UA塌陷的表现; 3）生理仪器和治疗干预的适当尺寸。猪UA的构成和功能与人类有相当大的相似性，自发性OSA发生在肥胖小型猪。肥胖的小型猪是特别合适的，因为超重和肥胖是OSA发展的最强风险因素，也是人类OSA的独立预测因子。这个有前途的模型尚未被评估为UA崩溃在OSA。建立一个有效的大型动物模型将是我们理解舌根和软腭在呼吸中的重要功能和形态的基础，将有助于改善呼吸障碍的临床治疗，将允许研究机械和外科治疗方式的纵向后果，并且能够在良好控制的实验条件下评估有争议的疗法，例如神经肌肉刺激和药理学应用。因此，我们提出了这项探索性研究，建立一个肥胖的小型猪模型用于OSA的研究，并确定舌根，软腭，咽壁的UA功能和崩溃在睡眠中的作用。我们将首先验证肥胖小型猪中的OSA，验证对照中的OSA不存在，并确定OSA中的阻塞部位以检验肥胖小型猪存在自发性OSA伴UA塌陷，而非肥胖对照没有OSA迹象的假设（目的1）。使用这些经验证的OSA动物，我们将通过比较对照组和患有OSA的肥胖小型猪的舌根和软腭的形态学和活动性来确定肥胖导致UA塌陷的物理机制，以检验以下假设：与对照组相比，肥胖OSA小型猪在舌根、软腭、 和咽壁，这反过来又会压缩UA并增加其在睡眠期间的呼吸阻力（目的2）。本研究将建立一种具有良好形态学和功能学特征的OSA动物模型，为OSA的多领域研究奠定基础。