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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 流行病学研究表明，过度活跃膀胱的尿症状在绝经后妇女中变得越来越普遍。雌激素治疗减轻这些症状的发现突出了过度活跃的膀胱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的不协调功能，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的影响有很多报道，但尚未报道过关于膀胱平滑肌中离子通道表达的雌激素调节的研究。膀胱的填充机理是肌源性的，因此在备案期间增加了膀胱肌细胞中的K+通道活性，可稳定膜电位并放松膀胱平滑肌。此外，雌激素水平较低引起的K+通道表达降低可以解释绝经后过度活跃的膀胱。我们先前已经表明，伸展依赖性的K+（SDK）通道以膀胱心肌细胞表示，并在填充过程中贡献调节膀胱依从性的肌源性机制。作为分子候选者，TREK-1通道具有与天然SDK通道相同的特性（单位电导，药理学和机械敏感性），并在人和鼠膀胱肌细胞中表达。因此，应将鼠膀胱视为研究SDK通道在人体膀胱依从性中的作用的合适模型。雌激素受体通过调节转录过程起作用，从而导致靶基因表达的调节。因此，我们将追求离子通道上雌激素调节的分子机制，尤其是Trek-1表达，以了解绝经后妇女中过度活跃膀胱的现象。该研究将检验以下假设：膀胱中的Trek-1通道表达取决于雌激素调节的基因组影响，而膀胱功能受损是雌激素对表达的TREK-1调节的结果。我们将采用电生理学，分子生物学和体内功能实验来定义雌激素水平的变化与对照和卵巢切除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。该提案的结果将突出trek-1通道在稳定膀胱填充过程中稳定膜电位的重要性，并将为绝经后女性的过度活跃膀胱提供新的特定目标。