钠钙交换体亚型NCX3在膀胱起搏细胞（ICC）兴奋调控中的作用及机制研究

Abnormality of detrusor excitation can cause many functional diseases. traditional neurogenic/myogenic hypotheses and agents owe unsatisfactional results. the studies on bladder-original excitation would be important. Bladder ICC can pacemake, and play the central role in bladder excitation initiation and integration. excitational pathways correlating to the calcium ions are considered to participate in the excitation initiation, calcium influx, calcium concentration regulation and calcium-activated signals in bladder ICC. Sodium/calcium exchanger (NCX）is important to maintain the intracellular calium concentration. We have confirmed the expression of NCX3 in bladder ICC, which can triger the increase of intracellular calcium concentration by its reverse mode, and be the important basis of excitation in bladder ICC. However, its mechanism in biological and pathological condition is still unclarified. In this study, the expression and function of bladder NCX3 will be first detected, and the NCX3 in bladder ICC will be up-regulated in normal bladder, and down-regulated in DI bladder, and their effect on the calcium concentration and ICC excitation will be evaluated. Moreover, the mTOR pathway will be interrupted via siRNA/knock out, followed by up-regulation of NCX3, to illustrate the mechanism of mTOR in the regulation of NCX3 on the bladder excitaion. This study will provide a brand new strategy for the treatment of bladder excitaion abnormalities.

逼尿肌兴奋异常可致多种功能性疾病。经典的神经/肌源性学说和神经受体药物临床疗效不佳,有关膀胱自身兴奋研究具有重要意义。膀胱ICC细胞具有起搏样功能，是膀胱兴奋起源和整合的枢纽。其中与钙离子相关的多种兴奋通路被发现广泛参与了其兴奋的起搏、钙离子入胞、胞内钙调控和钙源性兴奋信号。钠钙交换体（NCX）是维持细胞内钙离子浓度的重要机制。我们已证实膀胱ICC细胞表达有NCX3，其反向模式引发的细胞内钙离子浓度增高，是ICC细胞兴奋的重要基础，但生理及病理状态下如何维持膀胱ICC细胞钙浓度尚不明确。本项目拟检测膀胱ICC细胞中NCX3的表达及功能，并通过正向调控正常膀胱，以及反向调控DI膀胱ICC细胞NCX3，观察其对钙浓度及兴奋调控的影响，并进而通过干预mTOR通路，研究NCX作用于钙浓度的可能机制，以期系统阐明NCX3在膀胱ICC细胞兴奋调控中的作用及机制，为临床治疗膀胱兴奋异常疾病提供新策略。

逼尿肌兴奋异常可致多种功能性疾病。经典的神经/肌源性学说和神经受体药物临床疗效不佳,有关膀胱自身兴奋研究具有重要意义。膀胱ICC 细胞具有起搏样功能，是膀胱兴奋起源和整合的枢纽。其中与钙离子相关的多种兴奋通路被发现广泛参与了其兴奋的起搏、钙离子入胞、胞内钙调控和钙源性兴奋信号。钠钙交换体（NCX）是维持细胞内钙离子浓度的重要机制。我们已证实膀胱ICC 细胞表达有NCX3，其反向模式引发的细胞内钙离子浓度增高，是ICC 细胞兴奋的重要基础，但生理及病理状态下如何维持膀胱ICC 细胞钙浓度尚不明确。本项目拟检测膀胱ICC 细胞中NCX3 的表达及功能，并通过正向调控正常膀胱，以及反向调控DI 膀胱ICC 细胞NCX3，观察其对钙浓度及兴奋调控的影响，并进而通过干预mTOR 通路，研究NCX 作用于钙浓度的可能机制，以期系统阐明NCX3 在膀胱ICC 细胞兴奋调控中的作用及机制，为临床治疗膀胱兴奋异常疾病提供新策略。