Anatomical Specializations of the Human Pharynx

描述(由申请人提供)：此次续签是最近重新安置在哈肯萨克大学医学中心的PI工作的扩展。本研究旨在探讨特发性帕金森病患者吞咽困难的神经基础。帕金森病的吞咽困难通常被认为是继发于疾病相关的运动迟缓和强直。然而，对于帕金森病患者影响肢体功能的主要临床特征，抗帕金森病药物和手术干预措施是有效的，但对吞咽困难的治疗并没有产生一致或积极的效果。这些临床发现表明，帕金森病患者的口咽吞咽困难可能不仅仅与基底节多巴胺活性降低有关。其他神经递质系统或非多巴胺能机制也可能参与其中。我们假设帕金森病患者的口咽吞咽困难与咽部感觉-运动结构的生物和神经化学变化有关。感觉神经的神经改变可损害反射性吞咽的启动，而运动神经的神经改变可导致肌肉收缩缓慢。我们还假设，可能的神经病理变化，如变性诱导的神经纤维丢失或含有神经纤维的特定神经肽的减少，可能以神经依赖或组织区域特异性的方式发生。具体地说，由X神经支配的咽粘膜的不同区域(咽侧壁、会厌区、环状软骨后区和踝关节区)和肌肉(咽缩肌的快速外层)主要受到影响。这一假说得到了我们的新发现的支持，我们的新发现表明，触发口咽吞咽的咽粘膜和咽缩肌的吞咽相关快外层(FOL)主要由X神经分支支配。重要的是，我们的初步研究也为FOL选择性参与PD提供了证据。我们发现PD咽部的FOL由于肌球蛋白重链(MHC)由快变慢而变得非常缓慢。这些假设将通过以下两个具体目标进行检验。目的1探讨帕金森病患者咽部粘膜和肌纤维的感觉神经、运动神经和轴突终末的形态计量学和神经化学变化。将测定供应咽粘膜的上皮内神经纤维密度和神经肽免疫反应神经纤维的变化。支配咽部和舌部肌肉的运动神经和终板的变化也将使用定量技术记录下来。具体目标2是确定帕金森病患者咽部和舌部的肌肉变化。将使用形态学、免疫细胞化学和电泳法分析肌肉质量、纤维大小、酶组织化学活性、纤维类型和MHC表达模式。这些数据对于更好地理解帕金森病吞咽困难的病理生理机制以及开发治疗这种危及生命的疾病的新疗法至关重要。 公共卫生相关性：虽然特发性帕金森氏病(PD)会导致吞咽困难，影响数百万美国人，但吞咽困难的病理生理机制尚不清楚。这项拟议的工作是为了验证我们的假设，即帕金森病引起的吞咽困难与口腔和咽部支配吞咽相关结构的感觉神经纤维和运动神经纤维的退行性变化有关。这项研究将为神经源性吞咽困难提供生物学基础，这对开发治疗这种疾病的新疗法至关重要。

DESCRIPTION (provided by applicant): This renewal is an expansion of work by the PI who recently relocated at Hackensack University Medical Center. This proposal focuses on exploring neural basis of dysphagia in idiopathic Parkinson's disease (PD). Dysphagia in PD is generally considered secondary to disease-related bradykinesia and rigidity. However, anti-PD drugs and surgical interventions, which are efficacious for the treatment of the primary clinical features affecting the limb function in PD, are not found to produce consistent or positive effects in the treatment of the dysphagia. These clinical findings suggest that oropharyngeal dysphagia in PD may not be linked solely to a reduction in basal ganglia dopamine activity. Other neurotransmitter systems or nondopaminergic mechanisms may also be involved. We hypothesized that oropharyngeal dysphagia in PD is associated with biological and neurochemical changes in the sensori-motor structures of the pharynx. The neural alterations in the sensory nerves could impair initiation of reflex swallowing, whereas those in the motor nerves could result in slowness of muscle contraction. We also hypothesized that the possible neuropathological changes such as degeneration-induced nerve fiber loss or a deduction in specific neuropeptide containing nerve fibers may occur in a nerve-dependent or tissue region-specific manner. Specifically, distinct regions of pharyngeal mucosa (lateral pharyngeal walls, epiglottis, postcricoid and arytenoids regions) and muscles (fast out layer of the pharyngeal constrictors) innervated by the X nerve are predominantly affected. This hypothesis gains support from our new findings which showed that both the pharyngeal mucosa triggering oropharyngeal swallowing and the swallowing-related fast out layer (FOL) of the pharyngeal constrictor muscles are innervated mainly by the branches derived from the X nerve. Importantly, our pilot studies also provided evidence for the selective involvement of the FOL in PD. We found that the FOL in PD pharynx became very slow as a result of fast-to-slow myosin heavy chain (MHC) transformation. These hypotheses will be tested with the following 2 specific aims. Specific Aim 1 is to explore morphometric and neurochemical changes in the sensory and motor nerves and axon terminals innervating the mucosa and muscle fibers in PD pharynx. Changes in the intraepithelial nerve fiber density and neuropeptide immunoreactive nerve fibers supplying the pharyngeal mucosa will be determined. Alterations in the motor nerves and endplates innervating the pharyngeal and tongue muscles will be also documented using quantitative techniques. Specific Aim 2 is to determine muscular alterations in the PD pharynx and tongue. The muscle mass, fiber size, enzyme- histochemical activities, fiber type and MHC expression patterns will be analyzed using morphological, immunocytochemical and electrophoretic techniques. The data are critical for a better understanding of the pathophysiological mechanisms of dysphagia in PD and for the development of novel therapies to treat this life-threatening disorder. PUBLIC HEALTH RELEVANCE: While idiopathic Parkinson's disease (PD) results in dysphagia which affects millions of Americans, the pathophysiological mechanisms of dysphagia are poorly understood. The proposed work is to test our hypothesis that PD-induced dysphagia is associated with degenerative changes in both the sensory and motor nerve fibers innervating swallowing-related structures in the oral and pharyngeal regions. This research will provide biological basis of neurogenic dysphagia which is critical for the development of novel therapies to treat this disorder.