Neuromuscular Specializations of the Human Soft Palate

 描述(申请人提供)：人类软腭是一种极易移动的结构，在呼吸、吞咽和说话中起着关键作用。其功能障碍会导致睡眠呼吸暂停、吞咽困难和构音障碍。阻塞性睡眠呼吸暂停(OSA)患者在睡眠时软腭塌陷很常见，OSA是一种潜在威胁生命的疾病，影响着数百万美国人。这项研究的长期目标是开发治疗阻塞性睡眠呼吸暂停综合征的新型神经调节疗法。在过去的20年里，我们一直专注于研究人类上呼吸道(舌头、喉咙和咽部)的特殊变化。我们对舌头和舌下神经的研究结果直接适用于OSA的Inspire疗法的开发，OSA是FDA批准的一种用于舌头的电子“起搏”设备。虽然这种刺激器对许多患者有效，但已被发现对软腭塌陷的患者完全无效。这些患者属于最严重的患者之一，心脏病发作和中风的风险很高。我们相信，可以为这些患者开发出一种起搏设备。然而，电刺激的使用完全依赖于对感觉和运动神经解剖学的透彻了解。不幸的是，对腭咽闭合机制的神经控制知之甚少，因为软腭的神经支配长期以来一直存在争议。这项研究测试了一种假设，即人类软腭具有独特的神经肌肉特化，可能是为人类的言语、吞咽和上呼吸道呼吸功能而开发的。由于研究人体解剖学的独特方面只能在身体标本上进行，为此，我们开发了一种熟悉的和深奥的技术相结合的方法：Sihler‘s染色用于显示整个器官准备中的神经，乙酰胆碱酯酶和银染色法用于显示运动终板，免疫组织化学用于研究肌肉纤维类型，等等。具体目标1将决定人类软腭的神经专门化。将进行一系列研究，以：(1)绘制出整个神经的供应情况，确定神经肌肉的分区，并量化神经支配密度；(2)确定每块肌肉中的运动区并分析运动终板；(3)确定每块肌肉中运动单位的数量和大小；以及(4)对覆盖软腭部和咽侧壁的黏膜中的上皮内神经纤维密度和神经肽免疫反应神经纤维进行量化。具体目标2将描述人类腭部肌肉的内在特性。将进行以下研究：(1)测量特定纤维类型的氧化酶和糖酵解酶的活性；以及(2)分析每个肌肉和隔室的纤维类型和肌球蛋白重链组成。我们成熟的方法将展示人类软腭的神经肌肉特化及其延伸到咽壁和舌头。这项研究的结果有望直接用于开发治疗阻塞性睡眠呼吸暂停综合征的新疗法。

 DESCRIPTION (provided by applicant): The human soft palate is an extremely mobile structure that plays a critical role in breathing, swallowing, and speech. Disorders of its functio contribute to sleep apnea, dysphagia, and dysarthria. Soft palate collapse during sleep is commonly seen in patients with obstructive sleep apnea (OSA), a potentially life-threatening disorder affecting millions of Americans. The long-term goal of this research is to develop novel neuromodulation therapies to treat OSA. Over the last 20 years, we have focused on studying the specialized changes that have evolved in the human upper airway (tongue, larynx, and the pharynx). Findings from our work on the tongue and hypoglossal nerve have been directly applicable to the development of Inspire therapy for OSA, an FDA approved electrical "pacing" device for the tongue. Although effective for many patients, this stimulator has been found to be completely ineffective in those with soft palate collapse. These patients are among the most severe and are at high risk of heart attack and stroke. We believe that a pacing device can be developed for these patients. However, the use of electrical stimulation relies completely on a thorough knowledge of sensory and motor neuroanatomy. Unfortunately, neural control of the velopharyngeal mechanisms is poorly understood, as innervation of the soft palate has long been controversial. This research tests the hypothesis that the human soft palate has unique neuromuscular specializations presumably developed for human speech, swallowing, and upper airway respiratory function. As studying unique aspects of human anatomy can only be done with post mortem specimens, we have developed a combination of familiar and esoteric techniques for this purpose: Sihler's stain to visualize nerves in whole organ preparations, acetylcholinesterase and silver stain to visualize motor endplates, immunohistochemistry to study muscle fiber types, and others. Specific Aim 1 will determine the neural specializations of the human soft palate. A series of studies will be conducted to: (1) map out the entire nerve supply, define neuromuscular compartments, and quantify innervation densities; (2) localize motor zone within each muscle and analyze motor endplates; (3) determine the number and size of motor units in each muscle; and (4) quantify intraepithelial nerve fiber density and neuropeptide immunoreactive nerve fibers in the mucosa covering the soft palate and lateral pharyngeal walls. Specific Aim 2 will characterize the intrinsic properties of the human palatal muscles. Studies will be performed to: (1) measure the fiber type-specific activities of oxidative and glycolytic enzymes; and (2) analyze fiber type and myosin heavy chain composition in each muscle and compartment. Our well-established approach will demonstrate the neuromuscular specializations of the human soft palate and its extensions into the pharyngeal wall and tongue. The results from this research are expected to be directly transferable to the development of novel therapies to treat OSA.