Regulation of Urinary Bladder Smooth Muscle by K+ Channels

描述(申请人提供)：这个项目的长期目标是增加一个新的维度，使我们了解在正常和病理条件下调节人类膀胱功能的机制，并开发新的治疗策略来控制过度活跃的膀胱(OAB)。OAB，逼尿肌过度活动(DO)和相关的尿失禁(UI)，影响着大约17%的美国人口，其特征是膀胱平滑肌(UBSM)收缩能力增强。钾离子(K+)通道是最多样的离子通道超家族，是UBSM细胞膜兴奋性和动作电位的关键调节者，决定了UBSM收缩的时相性质。一般来说，抑制这些离子通道会导致膜兴奋性增加和时相收缩，而它们的激活会使细胞膜超极化，降低收缩能力。我们的基础科学研究小组与临床科学家合作，处于一个独特的地位，可以定期利用捐赠者患者的人类UBSM组织来研究人类的K+通道功能，并将基础科学发现与患者的尿动力学特征相关联。本项目的总体目标是阐明两个主要的K+通道，即小电导钙激活(SK)K+通道和中等电导钙激活K+(IK)通道在正常和病理条件下人类UBSM中的作用及其调节机制。这将验证SK/IK通道是人类UBSM兴奋性和收缩能力的主要调节者的新假设，因此SK/IK通道活性或调节机制的改变可能导致OAB/DO和相关的UI。此外，SK/IK通道可能为人类UBSM的新的药理操作和治疗干预提供了机会。特异性目标1将阐明在正常和病理生理条件下SK/IK通道在UBSM功能中的作用；特异性目标2将阐明2-肾上腺素能受体向SK/IK通道发出信号以促进UBSM松弛的机制。该项目将使用无症状膀胱(AUA症状评分8分；膀胱癌患者的膀胱切除术)、OAB(定义为频率增加、紧迫感和夜尿症)和DO(定义为尿动力学显示的过度活动)患者的UBSM组织。我们将采用一种结合的方法，使用最先进的技术来确定SK/IK通道的作用及其在UBSM功能中的调控机制，从单个分子和分离的细胞到完整的组织和整个生物体。 公共卫生相关性：膀胱过度活动症(OAB)影响了大约17%的美国人口，其特征是膀胱平滑肌收缩能力增强。我们的项目将利用膀胱组织中特定的钾通道来开发控制或缓解OAB的新疗法。

DESCRIPTION (provided by applicant): The long-term goal of this project is to add a new dimension to our understanding of the mechanisms that regulate human urinary bladder function under normal and pathological conditions and to develop novel therapeutic strategies to control overactive bladder (OAB). OAB, detrusor overactivity (DO), and related urinary incontinence (UI), which affects about 17% of the US population, is characterized with increased urinary bladder smooth muscle (UBSM) contractility. Potassium ion (K+) channels, the most diverse ion channel superfamily, are key regulators of UBSM cell membrane excitability and action potentials that determine the phasic nature of UBSM contractility. In general, inhibition of these ion channels leads to increased membrane excitability and phasic contractions, whereas their activation hyperpolarizes the cell membrane and decreases contractility. Our basic science research group, in collaboration with clinical scientists, is in a unique position to regularly make use of human UBSM tissues from donor patients in order to study K+ channel function in humans and correlate the basic science findings with the urodynamic profile of the patients. The overall goal of this project is to illuminate the role of two major K+ channels, the small conductance Ca2+-activated (SK) K+ channel and the intermediate conductance Ca2+-activated K+ (IK) channel, and their regulatory mechanisms in human UBSM under normal and pathological conditions. This proposal will test the novel hypothesis that the SK/IK channels are major regulators of human UBSM excitability and contractility, and therefore changes in the SK/IK channels activity or regulatory mechanisms may lead to OAB/DO and related UI. Furthermore, the SK/IK channels may represent an opportunity for novel pharmacological manipulation and therapeutic intervention in human UBSM. Specific Aim 1 will elucidate the role of the SK/IK channels in UBSM function under normal and pathophysiological conditions; and Specific Aim 2 will elucidate the mechanism by which 2-adrenergic receptors signal the SK/IK channels to promote UBSM relaxation. This project will use UBSM tissues from patients with asymptomatic bladder (AUA symptom score <8; cystectomy for bladder cancer), OAB (defined as increased frequency, urgency, and nocturia), and DO (defined as urodynamically demonstrated overactivity). We will employ a combined approach, using state-of- the-art techniques, to determine the role of SK/IK channels and their regulatory mechanisms in UBSM function from single molecules and isolated cells to intact tissue and the whole organism. PUBLIC HEALTH RELEVANCE: Overactive bladder (OAB) affects about 17% of the US population, and is characterized by increased urinary bladder smooth muscle contractility. Our project will exploit specific potassium channels in urinary bladder tissue to develop novel therapies to control or alleviate OAB.