NCX1调控食管壁肌间神经元nNOS活性及其在贲门失弛缓中的作用机制研究

贲门失弛缓是以食管下括约肌（LES）不能有效舒张为特征的食管运动障碍性疾病，其发病机制仍不明确，目前针对贲门失弛缓的治疗只能对症，研究阐明其发病机制具有重要科学意义。既往研究表明，食管壁肌间神经元nNOS在维持LES正常舒张中发挥重要作用，其调控功能失常是导致贲门失弛缓发生的关键。我们前期成功分离培养食管壁肌间神经元，发现NCX1在食管神经元表达并可感受机械性刺激促进外Ca2+内流，进而调控食管壁肌间神经元nNOS活性及LES的舒张。我们推测NCX1在食管壁肌间神经元正常调节功能至关重要，NCX1表达及功能的异常可能是导致LES舒张受限及贲门失弛缓发生的关键。本课题拟通过分子生物学、钙测定、膜片钳、基因模式动物等阐明NCX1调控LES舒张及其在贲门失弛缓中的作用及机制，证实NCX1调控通路的异常是导致贲门失弛缓发生发展的重要机制，为探寻贲门失弛缓治疗靶点及药物研发提供依据。

Achalasia is the functional disorder of esophageal motility characterized by ineffective relaxation of lower esophageal sphincter (LES). Since the specific etiology and pathogenesis are still unknown, the treatment of achalasia can only relieve the symptom. Therefore, it is of great significance to elucidate its pathogenesis. Previous research showed that nNOS of esophageal myenteric neurons played an important role in maintaining LES relaxation, while the impaired function of nNOS was critical for development of achalasia. We have successfully isolated and cultured the esophageal myenteric neurons, and found that the sodium calcium exchanger NCX1 was positively expressed in esophageal myenteric neurons, and could be activated by mechanical stimuli to enhance the calcium influx. And the increased calcium signaling further activated the nNOS activity and promoted the LES relaxation. Taken together, we speculated that the normal function of NCX1 in esophageal myenteric neurons was of great importance, and the abnormal expression and function of NCX1 may be the main cause of achalasia. This study will elucidate the function and mechanism of NCX1 in LES relaxation and achalasia using molecular biology, calcium recording, patch clamp and knockout mice. We sought to elucidate and confirm that the abnormal function of NCX1/Ca2+ signaling in esophageal myenteric neurons is the main mechanism for achalasia, and provide basic evidence for treatment and drug development of achalasia.