结直肠低敏感是慢性便秘患者无便意、直肠坠胀而排便困难的主要原因。骶神经刺激（SNS）可调节内脏敏感性，是慢性便秘很有前景的治疗方法，但机制不清。肠嗜铬（EC）细胞是肠粘膜感受器，具有机械传感功能，可通过释放5-HT将机械信号转变为化学信号。研究SNS对EC细胞机械传感功能的影响对优化SNS治疗及慢性便秘的发病研究有重要意义。TRPA1是EC细胞的感受器分子，前期研究发现TRPA1在慢性便秘结肠的表达降低。Piezo2是新近发现的机械敏感性离子通道，也表达于EC细胞，与TRPA1负责不同阈值的机械刺激。本课题拟在探讨Piezo2与TRPA1协同调节EC细胞机械传感的基础上，以EC细胞模型、慢性便秘大鼠、Piezo2与 TRPA1基因敲除小鼠为对象，研究SNS对结肠敏感性、结肠动力的影响，明确Piezo2/TRPA1介导的EC细胞机械传感途径在SNS干预中的作用，可望开启慢性便秘研究的新视野。

Chronic constipation is a common and distressing condition with no desire of defecation and difficulty in evacuation due to colorectal hyposensitiviey. Sacral nerve stimulation(SNS), regulating visceral sensitivity, is a promising treatment for chronic constipation with an unclear mechanism. Enterochromaffin (EC) cells are mechanosensors that respond to physical forces by translating the mechanical stimulus into an intracellular biochemical response leading to 5-HT release. Effect of SNS on EC cells mechanotransduction function is of great value for chronic constipation study. It has been proved that TRPA1 act as the sensor molecules of EC cells. Our previous study has revealed that the expression of TRPA1 mRNA and protein is significantly attenuated in the colon of patients with slow transit constipation. Recent studies have shown that the mechanosensitive ion channel Piezo2 is the primary mechanosensor in several specialized mechanosensory cells, including EC cells. Previous researches showed that Piezo2 alone appeared not sufficient to mediate the multitude of mechano-evoked phenomena in mechanotransduction. It might function as a low-threshold mechanical sensor in viscera physiologically. Based on the exploration of synergistic effect of Piezo2 and TRPA1 on the mechanotransduction of EC cells, we will use EC model cells, chronic constipation rat model and Piezo2/TRPA1 knockout mice to study the effect of SNS on the colonic sensitivity and motility that illuminate the role of SNS in the Piezo2/TRPA1 mediated EC cells mechanotransduction pathway, which promising a new perspective on the chronic constipation research.