STRETCH DEPENDENT POTASSIUM CHANNEL REGULATION IN OVERACTIVE BLADDER

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 流行病学研究表明，膀胱过度活动症的泌尿系统症状在绝经后妇女中更为常见。雌激素治疗可缓解这些症状的发现突出了膀胱过度活动症与雌激素水平的关系。动物实验证实，雌激素剥夺导致逼尿肌功能不协调，可通过雌激素治疗逆转。虽然有很多关于雌激素对膀胱功能的影响的报道，但关于雌激素对膀胱平滑肌离子通道表达的调节的研究还未见报道。膀胱的充盈机制是肌源性的，因此在充盈期间膀胱肌细胞中增加的K+通道活性稳定膜电位并松弛膀胱平滑肌。此外，低雌激素水平引起的K+通道表达减少可以解释绝经后膀胱过度活动症。我们先前已经表明，牵张依赖性K+（SDK）通道在膀胱肌细胞中表达，并有助于在充盈期间调节膀胱顺应性的肌源性机制。作为分子候选物，TREK-1通道具有与天然SDK通道相同的性质（单一电导、药理学特征和机械敏感性），并且在人和鼠膀胱肌细胞中表达。因此，鼠膀胱应被认为是研究SDK通道在人膀胱顺应性中的作用的合适模型。雌激素受体通过调节转录过程发挥作用，从而导致靶基因表达的调节。因此，我们将探讨雌激素调节离子通道的分子机制，特别是TREK-1的表达，以了解绝经后妇女膀胱过度活动症的现象。本研究将检验以下假设：膀胱中TREK-1通道表达由雌激素调节的基因组影响决定，膀胱功能受损是雌激素调节TREK-1表达的结果。我们将采用电生理学，分子生物学和体内功能实验，以确定雌激素水平的变化与TREK-1通道的表达，功能和基因调控的女性膀胱在控制和卵巢切除小鼠模型之间的联系。该提案的结果将突出TREK-1通道在膀胱充盈期间稳定膜电位的重要性，并将为绝经后女性膀胱过度活动症的治疗提供新的特异性靶点。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Epidemiological studies have shown that urinary symptoms of overactive bladder become more common in postmenopausal women. The finding that estrogen treatment alleviates these symptoms highlights the association of overactive bladder with estrogen levels. Animal experiments confirm that estrogen deprivation causes uncoordinated function of the detrusor which can be reversed through estrogen treatment. Although there are many reports on the effects of estrogen on bladder function, no study concerning estrogen regulation of ion channel expression in bladder smooth muscle has been reported. The filling mechanism of bladder is myogenic, thus increased K+ channel activity in bladder myocytes during filing stabilizes membrane potential and relaxes the bladder smooth muscle. Furthermore, reduced K+ channel expression caused by low estrogen levels could explain postmenopausal overactive bladder. We have previously shown that stretch- dependent K+ (SDK) channels are expressed in bladder myocytes and contribute the myogenic mechanisms regulating bladder compliance during filling. As a molecular candidate, TREK-1 channels have properties (unitary conductance, pharmacological profile, and mechanosensitivity) identical to native SDK channels and are expressed in human and murine bladder myocytes. Therefore murine bladder should be considered an appropriate model to study the role of SDK channels in human bladder compliance. Estrogen receptors act via the regulation of transcriptional processes, thus leading to regulation of target gene expression. Therefore we will pursue the molecular mechanism of estrogen regulation on ion channels, in particular TREK-1 expression, in order to understand the phenomenon of overactive bladder in postmenopausal women. This investigation will test the hypothesis that TREK-1 channel expression in bladder is determined by an estrogen-regulated genomic influence and that impaired bladder function is a result of TREK-1 modulation of expression by estrogen. We will employ electrophysiology, molecular biology, and in vivo functional experiments to define the link between alterations in estrogen levels with TREK-1 channel expression, function and gene regulation in female bladder in control and ovariectomized murine models. The results of this proposal will highlight the importance of TREK-1 channels in stabilizing the membrane potential during bladder filling and will provide a novel specific target in the treatment of overactive bladder in postmenopausal females.