Neuromuscular Specializations of the Human Soft Palate

人类软腭的神经肌肉特化

• 批准号: 9104358
• 负责人: LIANCAI MU
• 金额: $ 37.63万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9104358
• 关键词: Acetylcholinesterase; Affect; American; Anatomy; Animal Model; Area; Biochemical; Breathing; Calcitonin Gene-Related Peptide; Deglutition; Deglutition Disorders; Development; Devices; Disease; Dysarthria; Electric Stimulation; Electric Stimulation Therapy; Enzymes; FDA approved; Fiber; Functional disorder; Glycerol-3-Phosphate Dehydrogenase; Goals; Human; Hypoglossal nerve structure; Immunohistochemistry; Implant; Knowledge; Laryngeal Diseases; Larynx; Lateral; Life; Mammals; Maps; Measures; Medical; Methods; Motor; Motor Endplate; Mucous Membrane; Muscle; Muscle Fibers; Myocardial Infarction; Myosin Heavy Chains; Nerve; Nerve Fibers; Neuroanatomy; Neuropeptides; Obstructive Sleep Apnea; Organ; Palatal Muscles; Patients; Pattern; Pharyngeal structure; Play; Preparation; Property; Recruitment Activity; Reflex action; Research; Respiratory physiology; Role; Sensory; Sensory Nerve Endings; Series; Silver Staining; Sleep; Sleep Apnea Syndromes; Soft Palate; Specimen; Speech; Staining method; Stains; Stroke; Structure; Substance P; Succinate Dehydrogenase; Surface; System; Techniques; Testing; Tongue; Topical application; Work; afferent nerve; airway obstruction; density; high risk; intraepithelial; nerve supply; neuromuscular; neuroregulation; novel; novel therapeutics; peptide P; public health relevance; relating to nervous system; research and development; soft tissue

 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.

 描述（由申请人提供）：人类软腭是一种极其移动的结构，在呼吸、吞咽和言语中起着关键作用。其功能紊乱会导致睡眠呼吸暂停、吞咽困难和构音障碍。睡眠期间软腭塌陷常见于阻塞性睡眠呼吸暂停（OSA）患者，这是一种影响数百万美国人的潜在危及生命的疾病。这项研究的长期目标是开发新的神经调节疗法来治疗OSA。在过去的20年里，我们一直专注于研究人类上呼吸道（舌，喉和咽）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的电刺激疗法的开发，这是一种FDA批准的舌头电“起搏”装置。虽然对许多患者有效，但已发现这种刺激器对软腭塌陷的患者完全无效。这些患者是最严重的，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，神经控制的喉咽机制是知之甚少，神经支配的软腭一直是有争议的。这项研究测试的假设，人类软腭具有独特的神经肌肉专业化，可能是为人类的语音，吞咽和上呼吸道呼吸功能。由于研究人体解剖学的独特方面只能用死后标本来完成，我们为此开发了一种熟悉和深奥的技术组合：Sihler染色来可视化整个器官制备中的神经，乙酰胆碱酯酶和银染色来可视化运动终板，免疫组织化学来研究肌纤维类型等。具体目标1将确定人类软腭的神经特化。本研究将进行一系列的研究：（1）绘制整个神经供应图，确定神经肌肉分区，并量化神经支配密度;（2）定位每块肌肉内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;和（4）定量覆盖软腭和咽侧壁的粘膜中的上皮内神经纤维密度和神经肽免疫反应性神经纤维。具体目标2将描述人类腭肌的内在特性。将开展研究以：（1）测量氧化和糖酵解酶的纤维类型特异性活性;和（2）分析每个肌肉和隔室中的纤维类型和肌球蛋白重链组成。我们建立的方法将证明人类软腭及其延伸到咽壁和舌头的神经肌肉特化。这项研究的结果有望直接用于开发治疗OSA的新疗法。