Intrinsic Circadian Rhythms in Bladder

描述（由申请人提供）：BK大电导Ca+2依赖性K+通道是膀胱平滑肌（UBSM）收缩性的有效调节剂。Kcnma1-/-敲除小鼠，缺乏BK通道，表现出UBSM张力增加，过度活跃的收缩和不稳定的膀胱压力。这种膀胱过度活动导致Kcnma1-/-小鼠在睡眠期间尿失禁，这表明这些小鼠是夜尿症的一种新的啮齿动物模型，夜尿症是一种以睡眠期间过度排尿为特征的疾病。本提案的目的是确定BK通道如何参与排尿的日常调节，并对下尿路中控制正常昼夜（昼夜节律）排尿模式的鲜为人知的过程进行机制解释。与R21机制的目标一致，我们提出了一个高风险但高收益的假设，旨在揭示基于昼夜节律紊乱的夜尿症的全新理解。采用多学科方法，结合尿动力学测量与转基因分析，分子生物学和电生理学，BK通道在膀胱功能的日常调节中的作用将被解决。本研究的第一个具体目的是通过收缩性研究、电生理学记录BK电流和蛋白质表达分析来确定膀胱平滑肌在白天和夜间的功能差异。第二个具体目标是通过Kcnma1-/-和其他转基因小鼠系的膀胱测量来确定膀胱功能昼夜变化的机制，解决膀胱和中枢脑通路的相互作用。这些研究有可能确定一个根本的新机制和膀胱功能控制的新水平。所提出的研究对于阐明夜尿症患者治疗的关键机制具有重要意义。

DESCRIPTION (provided by applicant): The BK large conductance Ca+2-dependent K+ channel is potent regulator of urinary bladder smooth muscle (UBSM) contractility. Kcnma1-/- knockout mice, lacking the BK channel, exhibit increased UBSM tone, hyperactive contractions, and unstable bladder pressure. This bladder overactivity leads to urinary incontinence in Kcnma1-/- mice during the sleep period, suggesting that these mice are a novel rodent model for nocturia, a disorder characterized by excessive urination during the sleep period. The goal of this proposal is to determine how BK channels are involved in the daily regulation of voiding and develop a mechanistic explanation of the poorly understood processes in the lower urinary tract that govern the normal day-night (circadian) patterning of urine voiding. Consistent with the goals of the R21 mechanism, we propose a high- risk, but high-gain, hypothesis geared towards revealing a completely new understanding of nocturia that is based on the derangement of circadian rhythmicity. Using a multidisciplinary approach that combines urodynamic measurements with transgenic analysis, molecular biology, and electrophysiology, the role of the BK channel in the daily regulation of bladder function will be addressed. The first specific aim of the proposed work is to determine how bladder function is different between day and night in urinary bladder smooth muscle by contractile studies, recording of BK currents by electrophysiology, and analysis of protein expression. The second specific aim will determine the mechanism of a day-night change in bladder function by cystometry in Kcnma1-/- and other transgenic mouse lines, addressing the interaction of the bladder and central brain pathways. These studies have the potential to identify a fundamentally new mechanism and novel level of control for bladder function. The proposed studies are highly significant for elucidating critical mechanisms to target for the treatment of nocturia in human patients. PUBLIC HEALTH RELEVANCE: Nocturia, excessive urination at night, is a common and often persistent disorder affecting > 50% of people in some age groups and significantly decreasing quality of life. The goal of the proposed research is to develop a mechanistic explanation of the poorly understood processes that govern the normal day-night (circadian) pattern of urine voiding and that may go awry in nocturia.