STRETCH DEPENDENT POTASSIUM CHANNEL REGULATION IN OVERACTIVE BLADDER

膀胱过度活动症中拉伸依赖性钾通道调节

• 批准号: 8360520
• 负责人: SANG Don KOH
• 金额: $ 22.95万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360520
• 关键词: Animal Experiments; Bladder; Centers of Research Excellence; Electrophysiology (science); Epidemiologic Studies; Estrogen Receptors; Estrogens; Female; Funding; Gene Expression; Gene Expression Regulation; Genomics; Grant; Human; Investigation; Ion Channel; Link; Membrane Potentials; Modeling; Molecular; Molecular Biology; Mus; Muscle Cells; National Center for Research Resources; Overactive Bladder; Postmenopause; Potassium Channel; Principal Investigator; Process; Property; Regulation; Reporting; Research; Research Infrastructure; Resources; Role; Smooth Muscle; Source; Stretching; Symptoms; Testing; Transcriptional Regulation; United States National Institutes of Health; Woman; cost; deprivation; in vivo; novel; potassium channel protein TREK-1; research study; urinary

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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 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女性中更为常见。雌激素治疗可以缓解这些症状的发现凸显了膀胱过度活动症与雌激素水平的关联。动物实验证实，雌激素剥夺会导致逼尿肌功能不协调，这可以通过雌激素治疗来逆转。尽管关于雌激素对膀胱功能影响的报道较多，但尚未见雌激素调节膀胱平滑肌离子通道表达的研究报道。膀胱充盈机制是肌源性的，充盈过程中膀胱肌细胞K+通道活性增加，稳定膜电位，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。我们之前已经表明，拉伸依赖性 K+ (SDK) 通道在膀胱肌细胞中表达，并有助于调节充盈过程中膀胱顺应性的生肌机制。作为分子候选者，TREK-1 通道具有与天然 SDK 通道相同的特性（单一电导、药理学特征和机械敏感性），并在人类和小鼠膀胱肌细胞中表达。因此，小鼠膀胱应被视为研究 SDK 通道在人类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，从而调节靶基因表达。因此，我们将探讨雌激素调节离子通道，特别是TREK-1表达的分子机制，以了解绝经后女性膀胱过度活动症的现象。这项研究将检验以下假设：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，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来确定对照和卵巢切除小鼠模型中雌性膀胱中雌激素水平的变化与 TREK-1 通道表达、功能和基因调控之间的联系。该提案的结果将强调 TREK-1 通道在膀胱充盈过程中稳定膜电位的重要性，并将为绝经后女性膀胱过度活动症的治疗提供新的具体靶点。