Obstructive Sleep Apnea - An Obese Minipig Model

 描述(申请人提供)：舌根和软腭构成口咽的前缘，控制进入喉部的入口。因此，它们的大小，位置， 机动性对上呼吸道(UA)有重要影响。临床资料显示，阻塞性睡眠呼吸暂停或低通气(OSA)患者通常由于组织块过多或舌根和/或软腭的神经肌肉损害而出现UA的解剖损害。然而，关于舌根和软腭的形状和移动性如何导致睡眠期间UA崩溃的信息非常有限。由于必要的侵入性技术，人类研究无法解决阻塞性睡眠呼吸暂停的发病机制和病理生理学基础上的这些关键问题。因此，一个合适、可靠的动物模型势在必行。这个模型必须满足三个基本标准：1)解剖和功能与人类相似；2)出现自发性OSA伴UA崩溃；3)适合生理器械和治疗干预的大小。猪的尿酸组成和功能与人类有相当大的相似性，自发性阻塞性睡眠呼吸暂停发生在肥胖的小型猪身上。肥胖的小型猪特别合适，因为超重和肥胖是OSA发生的最强风险因素，也是人类OSA的独立预测因素。这个有希望的模型还没有在阻塞性睡眠呼吸暂停综合征的UA崩溃中进行评估。建立一个有效的大型动物模型将是我们了解呼吸过程中舌根和软腭的重要功能和形态的基础，将有助于改进呼吸障碍的临床治疗，将有助于研究机械和手术治疗方式的纵向后果，并将能够在良好控制的实验条件下评估有争议的治疗方法，如神经肌肉刺激和药物应用。因此，我们提出了一项探索性研究，旨在建立一种用于OSA研究的肥胖小型猪模型，并确定舌根、软腭和咽壁在睡眠中UA功能和崩溃中的作用。我们将首先验证肥胖小型猪的OSA，验证对照组中OSA的缺失，并确定OSA中的阻塞点(S)，以检验肥胖小型猪出现自发性OSA伴UA崩溃的假说，而非肥胖组没有OSA的迹象(目标1)。利用这些经过验证的OSA动物，我们将通过比较对照组和肥胖小型猪与OSA组舌根和软腭的形态和活动度来确定肥胖导致UA崩溃的物理机制，以检验这样的假设：与对照组相比，肥胖OSA小型猪表现出过多的质量和僵硬，活动能力降低，舌根、软腭、 和咽壁，这反过来压缩UA，并增加其在睡眠中对呼吸的阻力(目标2)。研究结果将为阻塞性睡眠呼吸暂停综合征的各个领域的研究提供一个合适的、可靠的、具有良好特征的UA动物模型。

 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.