STRETCH DEPENDENT POTASSIUM CHANNEL REGULATION IN OVERACTIVE BLADDER

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 流行病学研究表明，膀胱过度活动的尿路症状在绝经后妇女中变得更加常见。雌激素治疗可以缓解这些症状，这一发现突显了膀胱过度活跃与雌激素水平的关系。动物实验证实，雌激素缺乏会导致逼尿肌功能失调，这种失调可以通过雌激素治疗而逆转。虽然有关雌激素对膀胱功能影响的报道很多，但有关雌激素对膀胱平滑肌离子通道表达的调节作用的研究尚未见报道。膀胱充盈的机制是肌源性的，因此，膀胱肌细胞在充盈过程中K+通道活性增加，从而稳定了膜电位，松弛了膀胱平滑肌。此外，低雌激素水平导致的K+通道表达减少可以解释绝经后膀胱过度活跃的原因。我们先前已经证明，在充盈过程中，牵张依赖性K+(SDK)通道在膀胱肌细胞中表达，并参与调节膀胱顺应性的肌源性机制。作为一个候选分子，Trek-1通道具有与天然SDK通道相同的性质(单一电导、药理特性和机械敏感性)，并在人和小鼠膀胱肌细胞中表达。因此，小鼠膀胱应该被认为是研究SDK通道在人膀胱顺应性中作用的合适模型。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，以了解绝经后女性膀胱过度活跃的现象。这项研究将验证这样一种假设，即膀胱中Trek-1通道的表达是由雌激素调节的基因组影响决定的，而膀胱功能受损是雌激素调节Trek-1表达的结果。我们将利用电生理学、分子生物学和体内功能实验来确定雌激素水平的变化与对照和去卵巢小鼠模型中女性膀胱中Trek-1通道表达、功能和基因调控之间的联系。这项研究的结果将强调Trek-1通道在膀胱充盈过程中稳定膜电位的重要性，并将为治疗绝经后女性过度活跃的膀胱提供一个新的特异性靶点。

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.