Stretch Sensitive Neurons and Lower Esophageal Sphincter

拉伸敏感神经元和下食管括约肌

• 批准号: 8258195
• 负责人: RAVINDER K. MITTAL
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258195
• 关键词: Achalasia; Acids; Address; Area; Barrett Esophagus; Cephalic; Chest Pain; Complication; Deglutition; Disease; Electric Stimulation; Esophageal; Esophageal Diseases; Esophageal Stenosis; Esophagitis; Esophagus; Functional disorder; Fundoplication; Gastroesophageal reflux disease; Gastrointestinal tract structure; General Population; Goals; Health; Healthcare Systems; Heartburn; Hypertrophy; Inferior esophageal sphincter structure; Interstitial Cell of Cajal; Investigation; Laboratories; Larynx; Lead; Learning; Malignant neoplasm of esophagus; Mechanics; Mediating; Medical; Morbidity - disease rate; Motor; Motor Neurons; Mus; Muscle; Muscle Contraction; Myenteric Plexus; Neural Pathways; Neurons; Nutcracker Esophagus; Obstruction; Oral; Pain; Patients; Physiological; Play; Preganglionic Autonomic Fibers; Prevalence; Proton Pump Inhibitors; Publishing; Reflux; Relaxation; Resistance; Respiratory System; Respiratory tract structure; Role; Secondary to; Smooth Muscle Myocytes; Spastic; Sphincter; Stimulus; Stomach; Stretching; Students; Symptoms; Synapses; Synaptic Transmission; Thinking; Vagus nerve structure; Veterans; Work; abstracting; base; cost; improved; inhibitory neuron; motor disorder; muscle hypertrophy; pressure; response; treatment strategy

DESCRIPTION (provided by applicant): Abstract: Stretch Sensitive Neurons & Lower Esophageal Sphincter Relaxation The lower esophageal sphincter guards the entrance from the esophagus to the stomach, its incompetence (too much relaxation) leads to gastro-esophageal reflux (GER) and heartburn" which is one of the most prevalent medical conditions. The impaired LES relaxation (or little relaxation) is the hallmark of achalasia of the esophagus and possibly other spastic motor disorders of the esophagus. Therefore, it is quite apparent that LES dysfunction contributes to significant medical morbidity and health related costs. Our current understanding is that the LES relaxation is neurogenic; it result from activation of the inhibitory neurons located in the myenteric plexus. How does the inhibitory myenteric neuron gets activated is not entirely clear. Current thinking is that preganglionic fibers of the vagus nerve synapse with the inhibitory motor neuron of the LES. The inhibitory motor neuron is located in the myenteric plexus of the lower esophageal sphincter. Contrary to current paradigm, our preliminary studies suggest a role of axial stretch in the activation of the inhibitory myenteric neuron to the LES. Under physiologic conditions, the axial stretch of the LES is caused by esophageal longitudinal muscle contraction. Based on a large number of studies, it is felt that the interstitial cells of Cajal (ICC) mediate neural transmission between the myenteric neurons and smooth muscle cells. Furthermore, ICC's are thought to act as mechanosensors in the gastrointestinal tract. We plan to determine the role of ICC in stretch mediated responses in the LES. We hope that an improved understanding of the mechanism of LES relaxation will results in better strategies to treat reflux disease and spastic motor disorders of the esophagus. The specific goals of our studies are to determine: 1; the mechanism of stretch-activated responses in the mice lower esophageal sphincter - role of stretch sensitive neuron and ICC in the LES relaxation 2; the role of stretch sensitive neurons in the physiologic LES relaxation, i.e., swallow, balloon-distension and electrical stimulation of the vagus nerve induced LES relaxation 3; the effect of Nissen fundoplication on the axial stretch activated LES relaxation PUBLIC HEALTH RELEVANCE: Project Narrative: Significance and Relevance to Veterans Health: A large number of our veterans suffer from disorders of the esophagus; i.e., reflux disease and spastic motor disorders. Heartburn, regurgitation, chest pain and difficulty swallowing are some of the symptoms related to these disorders. The prevalence of reflux disease and associated complications resulting from reflux disease such as Barrett's esophagus and esophageal cancer is generally felt to be greater in the veterans as compared to general population. Lower esophageal sphincter or a "valve like" mechanism between the esophagus and stomach plays an important role in reflux disease and spastic motor disorders of the esophagus. Based on our observations, motor disorders of the esophagus are related to poor relaxation of the lower esophageal sphincter and the fundamental abnormality in reflux disease is too much relaxation of the lower esophageal sphincter. Therefore, a better understanding of the mechanisms of sphincter relaxation is likely to lead to better treatment strategies in all forms of esophageal motor dysfunctions. The goal of our studies is to enhance our understanding of the mechanism of lower esophageal sphincter relaxation.

描述（由申请人提供）： 摘要：拉伸敏感的神经元和下食管括约肌放松下部食管括约肌从食道到胃的入口，其无能（过多的放松）导致胃食管倒流（GER）和心脏最普遍，这是“这是最普遍的”医疗状况当前的理解是，LES弛豫是由位于Myenteric Plexus中的抑制性神经元激活的。 LES的抑制性运动神经元。与当前的范式相反，我们的初步研究表明，轴向拉伸在抑制性肌室神经元向LES激活中的作用。在生理条件下，LES的轴向拉伸是由食管纵向肌肉收缩引起的。 基于大量研究，人们认为Cajal（ICC）的间质细胞介导了骨膜神经元和平滑肌细胞之间的神经传播。此外，ICC被认为是胃肠道中的机械传感器。我们计划确定ICC在LES中拉伸介导的反应中的作用。我们希望对LES松弛机制的改进理解能够提供更好的策略来治疗食道的反流疾病和痉挛性运动障碍。我们研究的具体目标是确定：1​​;小鼠降低食管括约肌的拉伸激活反应的机制 - 拉伸灵敏神经元和ICC在LES弛豫2中的作用；拉伸敏感神经元在生理LES松弛中的作用，即吞咽，气球距离和迷走神经诱导的LES弛豫的电刺激3； Nissen底折对轴向拉伸激活LES松弛的影响 公共卫生相关性： 项目叙述：与退伍军人健康的意义和相关性：我们的大量退伍军人患有食道疾病；即反流疾病和痉挛运动障碍。胃灼热，反流，胸痛和吞咽困难是与这些疾病有关的一些症状。与普通人群相比，退休疾病（如巴雷特食管和食管癌）所引起的反流疾病的流行和相关并发症通常更大。食管和胃之间的食道括约肌或“类似瓣膜”的机制在食道的反流疾病和痉挛性运动障碍中起着重要作用。根据我们的观察结果，食管的运动障碍与低食管括约肌的松弛不良有关，而反流疾病的基本异常对下食管括约肌的放松过多。因此，更好地了解括约肌松弛机制可能会导致各种形式的食管运动功能障碍的更好的治疗策略。我们研究的目的是增强我们对较低食管括约肌松弛机制的理解。