Intrinsic Circadian Rhythms in Bladder

描述（由申请方提供）：BK大电导Ca+2依赖性K+通道是膀胱平滑肌（UBSM）收缩性的强效调节剂。缺乏BK通道的Kcnma 1-/-敲除小鼠表现出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Kcnma 1-/-小鼠在睡眠期间出现尿失禁，这表明这些小鼠是夜尿症的新型啮齿动物模型，夜尿症是一种以睡眠期间排尿过多为特征的疾病。该提案的目标是确定BK通道如何参与排尿的日常调节，并对下尿路中控制尿液排尿的正常昼夜（昼夜节律）模式的知之甚少的过程进行机械解释。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，旨在揭示一个全新的理解，是基于昼夜节律紊乱的睡眠障碍。使用多学科的方法，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通道在日常调节膀胱功能的作用将得到解决。建议的工作的第一个具体目标是通过收缩研究，记录BK电流的电生理学和蛋白质表达的分析来确定膀胱功能在膀胱平滑肌中的昼夜差异。第二个具体目标是通过膀胱测压法确定Kcnma 1-/-和其他转基因小鼠系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全新的机制和新的膀胱功能控制水平。所提出的研究对于阐明靶向治疗人类患者的糖尿病的关键机制具有重要意义。 公共卫生相关性：夜尿症，即夜间排尿过多，是一种常见且经常持续的疾病，影响某些年龄组中> 50%的人，并显着降低生活质量。拟议研究的目标是对管理尿液排泄的正常昼夜（昼夜节律）模式以及可能在排尿中出错的知之甚少的过程进行机械解释。

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.