Mechanosensory Motor Neurons of Lower Esophageal Sphincter

描述（由申请人提供）： 引言：食管下括约肌（LES）松弛受损是贲门失弛缓症和其他食管痉挛性运动障碍的标志。过多的LES松弛（一过性LES松弛）导致反流病。因此，很明显LES功能障碍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，由迷走神经介导，迷走神经与位于食管肌间神经丛中的抑制性运动神经元突触。假设：我们的假设是，迷走神经不与抑制性运动神经元突触，而是由食管的纵向肌肉收缩引起的机械牵拉通过牵拉敏感机制激活位于肌间神经丛中的抑制性运动神经元。这些抑制性运动神经元释放一氧化氮和可能的其他神经递质，以响应拉伸并引起LES的松弛。目的：本研究的具体目标是：1）从大鼠食管肌间神经丛分离神经元，并确定它们是否对机械刺激，即，拉伸，并释放神经递质，如一氧化氮和乙酰胆碱。此外，我们将确定牵张介导的食管运动神经元激活的机制。（2）用顺行神经示踪技术观察迷走神经分支与LES抑制性运动神经元是否存在突触。3）通过多光子显微镜绘制肌间神经丛中介导LES松弛的神经回路。临床关系：大量的退伍军人患有食道疾病。LES是食管和胃之间的“瓣膜样”机制。食管运动障碍与LES松弛不良有关，反流病的基本异常是LES松弛过度。因此，更好地了解LES松弛的机制可能会导致更好的治疗策略，在所有形式的食管运动功能障碍。影响/意义：我们希望通过对LES松弛机制的进一步了解，能够为治疗食管反流性疾病和痉挛性运动障碍提供更好的策略。

DESCRIPTION (provided by applicant): Introduction: Impaired lower esophageal sphincter (LES) relaxation is the hallmark of achalasia and other spastic motor disorders of the esophagus. Too much LES relaxation (transient LES relaxation) leads to reflux disease. Therefore, it is quite clear that LES dysfunction contributes o significant medical morbidity and health related costs. Our current understanding is that the LES relaxation is neurogenic, mediated by vagus nerve which synapses with the inhibitory motor neurons located in the myenteric plexus of the esophagus. Hypothesis: Our hypothesis is that vagus nerve does not synapse with inhibitory motor neurons, rather it is the mechanical stretch caused by longitudinal muscle contraction of the esophagus that activates the inhibitory motor neurons located in the myenteric plexus through a stretch sensitive mechanism. These inhibitory motor neurons release nitric oxide and possibly other neurotransmitters in response to stretch and cause relaxation of the LES. Aim: The specific goals of our studies are: 1).To isolate neurons from the myenteric plexus of the rat esophagus and determine if they respond to mechanical stimulus, i.e., stretch, and release neurotransmitters such as nitric oxide and acetylcholine. Furthermore, we will determine the mechanism of stretch mediated activation of esophageal motor neurons. 2).To determine if vagus nerve branches synapse with the inhibitory motor neurons of the LES using anterograde neural tracer techniques. 3).To map the neural circuit in the myenteric plexus that mediates LES relaxation by multiphoton microscopy. Clinical Relationships: A large number of veterans suffer from the disorders of the esophagus. LES is a "valve like" mechanism between the esophagus and stomach. Motor disorders of the esophagus are related to poor relaxation of the LES and the fundamental abnormality in reflux disease is too much relaxation of the LES. Therefore, a better understanding of the mechanisms of LES relaxation is likely to lead to better treatment strategies in all forms of esophageal motor dysfunctions. Impact/Significance: 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.