膀胱过度活动症（OAB）发病率高病因复杂，ICC细胞为核心的逼尿肌过度活动（DO）是其发生的重要基础，而HCN介导的Ih起搏电流异常是核心机制。我们前期发现DO膀胱上调的神经降压素（NTs）可以结合激活NTSR1，进一步促进ICC细胞HCN通道开放，增强膀胱自发兴奋性；小窝结构域内的小窝蛋白3（Caveolin-3）活化是小窝结构调控HCN通道表达和活性的分子基础；而NTSR1则可通过与胞浆内的Caveolin-3蛋白结合，促进其棕榈化修饰，转位至小窝内活化，而NTs是否通过Caveolin-3调控HCN活性尚不清楚。据此提出假说，DO时上调的NTs激活NTSR1促Caveolin-3棕榈化转位，上调HCN通道活性，增强膀胱自发兴奋性。本研究拟通过正/反向调控Caveolin-3表达和棕榈化，阐明NTs调控HCN通道在DO膀胱兴奋性异常中的作用及机制，为DO的基础研究和临床治疗提供新思路。

Overactive bladder(OAB) is a very common clinical bladder dysfunction which has high incidence and complicated pathogenesis. The dysfunction of ICC cells is the basis of bladder detrusor overatvity (DO), and the dysfunction of hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN) mediated Ih current is the key molecular mechanism. Our previous researches have showed that neurotensin can up-regulate HCN channel activity via binding and activating NTSR1 to increase the bladder spontaneous excitability; Activation of caveolin-3 localized in caveolae is the molecular basis of regulating HCN channel expression and function levels；NTSR1 can bind and promote caveolin-3 palmitoylating and translocating onto caveolae for activation.However, whether the NTs can regulate HCN channel opening via activating caveolin-3 is not clear. Accordingly, we hypothesized that up-regulated neurotensin in DO can abnormally increase HCN channel via NTSR1/caveolin-3 pathway to increase bladder excitability. In this study, we will aim to illustrate the molecular mechanism of the regulation of neurotensin on HCN channel, and determine the role of caveolin-3 activated by NTSR1 in the pathological process of DO by applying gene knockout, lentivirus overexpression and RNAi silencing. Illustrating the underlying mechanism systematically might optically bring us new strategies for medical research and clinical treatment of detrusor overactivity.