Stretch Sensitive Neurons and Lower Esophageal Sphincter

描述(由申请人提供)： 摘要：伸展敏感神经元与下食道括约肌松弛食道下括约肌守卫着从食道到胃的入口，其功能不全(过度松弛)会导致胃食道反流(GER)和烧心，这是最常见的内科疾病之一。LES松弛受损(或很少松弛)是食道失弛缓症和其他可能的食道痉挛运动障碍的标志。因此，很明显，LES功能障碍会导致显著的医疗发病率和健康相关成本。我们目前的理解是，LES松弛是神经源性的；它是由肌间神经丛中的抑制性神经元激活所致。抑制性肌间神经元是如何被激活的还不完全清楚。目前的想法是迷走神经的节前纤维与LES的抑制性运动神经元突触。抑制性运动神经元位于下食道括约肌的肌间神经丛中。与目前的范式相反，我们的初步研究表明，轴向拉伸在激活LES的抑制性肌间神经元中发挥了作用。在生理条件下，LES的轴向拉伸是由食道纵行肌肉收缩引起的。大量研究认为，Cajal间质细胞(ICC)在肌间神经元和平滑肌细胞之间介导神经传递。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牵张调节反应中的作用。我们希望，对LES松弛机制的更好理解将导致更好的治疗反流病和食道痉挛运动障碍的策略。本研究的具体目的是确定：1、小鼠下食道括约肌牵拉激活反应的机制--拉伸敏感神经元和ICC在LES松弛中的作用；2、拉伸敏感神经元在生理性LES松弛中的作用，即吞咽、气囊扩张和电刺激迷走神经引起的LES松弛；3、尼森胃底折叠术对轴向牵张激活的LES松弛的影响。 公共卫生相关性： 项目简介：对退伍军人健康的意义和相关性：我们的退伍军人中有大量患有食道疾病，即反流性疾病和痉挛运动障碍。胃灼热、反胃、胸痛和吞咽困难是与这些疾病相关的一些症状。退伍军人普遍认为，与普通人群相比，退伍军人的反流病及其相关并发症(如Barrett‘s食道和食道癌)的患病率更高。下食道括约肌或食道与胃之间的“瓣膜状”机制在反流病和食道痉挛运动障碍中起着重要作用。根据我们的观察，食道运动障碍与下食道括约肌松弛不良有关，反流病的基本异常是下食道括约肌过度松弛。因此，更好地了解括约肌松弛的机制可能会导致更好的治疗策略来治疗各种形式的食道运动功能障碍。我们研究的目的是为了加深我们对下食道括约肌松弛机制的理解。

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.