Molecular basis for mechanosensitivity of esophageal enteric neurons (EMN)

食道下括约肌(LES)松弛受损是失弛缓症的特点。 以及食道痉挛运动障碍。另一方面，过度的LES松弛(瞬时LES 松弛)会导致反流病。因此，LES功能障碍会导致严重的发病率和健康问题。 相关成本。我们目前的理解是LES的松弛是由迷走神经介导的神经源性的。 它与肌间神经丛的抑制性运动神经元突触。假设：我们的假设是 迷走神经与食道纵肌的兴奋性神经突触，是 由纵向肌肉收缩引起的机械拉伸，激活位于 肌间神经丛通过机械敏感(拉伸敏感)机制。我们将鉴定分子 肌间神经元的机械敏感性的候选。目标：我们的具体目标 研究内容如下：1)检测TRPV4作为机械敏感分子在食道肌间神经元中的作用 (EMN)；检测NCX1作为肌动蛋白的机械敏感分子；3)确定TRPV4和 NCX1在EMN的机械敏感性方面具有协同作用。 临床关系：大量退伍军人患有反流病和痉挛运动障碍 食道，我们认为LES功能障碍在以上两种疾病中都起主要作用。更好的 对食道蠕动和LES松弛的神经控制的了解可能会导致更好的 各种食道运动障碍的治疗策略。影响/意义：我们希望 了解中枢和外周控制食道和LES运动功能的机制 结果在治疗反流病和食道痉挛障碍方面有了更好的策略。

Introduction: Impaired lower esophageal sphincter (LES) relaxation is the hallmark of achalasia esophagus and spastic motor disorders of the esophagus. On the other hand, excessive LES relaxation (transient LES relaxation) leads to reflux disease. Therefore, LES dysfunction contributes to significant 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 of the myenteric plexus. Hypothesis: Our hypothesis is that the vagus nerve synapse with the excitatory nerves of the longitudinal muscles of the esophagus and it is the mechanical stretch caused by longitudinal muscle contraction that activates inhibitory motor neurons located in the myenteric plexus through a mechanosensitive (stretch-sensitive) mechanism. We will identify the molecular candidates for the mechanosensitive property of the myenteric neurons. Aim: The specific goals of our studies are: 1).To examine TRPV4 as a mechanosensitive molecule of the esophageal myenteric neurons (EMN); 2). To examine NCX1 as a mechanosensitive molecule of the EMN; 3).To determine if TRPV4 and NCX1 are synergistic in the mechanosensitivity of the EMN. Clinical Relationships: A large number of veterans suffer from reflux disease and spastic motor disorders of the esophagus and we believe that LES dysfunction plays a major role in both of the above. A better understanding of the neural control of esophageal peristalsis and LES relaxation is likely to lead to better treatment strategies in various esophageal motor disorders. Impact/Significance: We hope that an improved understanding of the mechanism of central and peripheral control of esophagus and LES motor function will results in better strategies to treat reflux disease and spastic disorders of the esophagus.