Mechanosensory Motor Neurons of Lower Esophageal Sphincter

描述(由申请人提供)： 导语：下食道括约肌(LES)松弛受损是失弛缓症和其他食道痉挛运动障碍的标志。过多的LES松弛(一过性LES松弛)会导致反流病。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，由迷走神经介导，迷走神经与位于食道肌间神经丛的抑制性运动神经元突触。假设：我们的假说是，迷走神经不与抑制性运动神经元突触，而是由食道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的抑制性运动神经元。这些抑制运动神经元释放一氧化氮和可能的其他神经递质作为对拉伸的反应，并导致LES的松弛。目的：我们研究的具体目标是：1)分离大鼠食道肌间神经丛中的神经元，并确定它们对机械刺激(即拉伸)是否有反应，并释放神经递质，如一氧化氮和乙酰胆碱。此外，我们还将确定牵张介导的食道运动神经元激活的机制。2)应用顺行神经示踪技术确定迷走神经分支是否与LES抑制性运动神经元突触。3).用多光子显微镜定位肌间神经丛中介导LES松弛的神经回路。临床关系：大量退伍军人患有食道疾病。LES是食道和胃之间的一种“瓣膜状”机制。食道运动障碍与LES松弛不良有关，反流病的基本异常是LES过度松弛。因此，更好地了解LES松弛的机制可能会导致更好的治疗各种形式的食道运动功能障碍的策略。影响/意义：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。

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.