Intrinsic Circadian Rhythms in Bladder

膀胱的内在昼夜节律

• 批准号: 7977915
• 负责人: Andrea L Meredith
• 金额: $ 20.12万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7977915
• 关键词: Address; Affect; Bladder; Bladder Control; Brain; Circadian Rhythms; Contractile Proteins; Data; Disease; Electrophysiology (science); Etiology; Exhibits; Exploratory/Developmental Grant; Frequencies; Functional disorder; Gene Expression; Genes; Goals; Harvest; Human; Hypothalamic structure; Incontinence; Investigation; Kidney; Knockout Mice; Knowledge; Link; Lower urinary tract; Measurement; Membrane; Molecular Biology; Mus; Muscle Tonus; Mutation; Nerve; Neurons; Nocturia; Outcomes Research; Pathology; Patients; Pattern; Periodicity; Peripheral; Phenotype; Polyuria; Potassium Channel; Process; Property; Quality of life; Regulation; Research; Rodent; Rodent Model; Role; Sleep; Smooth Muscle; Smooth Muscle Myocytes; Testing; Time; Transgenic Mice; Transgenic Organisms; Tropomyosin; Urinary Incontinence; Urination; Urine; Urodynamics; Variant; Work; age group; base; brain pathway; calponin; high risk; interdisciplinary approach; interest; large-conductance calcium-activated potassium channels; mouse model; novel; pressure; protein expression; public health relevance; research study

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.

描述(申请人提供)：BK大电导钙依赖的K+通道是膀胱平滑肌(UBSM)收缩的强有力的调节器。Kcnma1/-基因敲除小鼠缺乏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。这项建议的目的是确定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)排尿模式的鲜为人知的过程提出机械解释。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说，旨在揭示基于昼夜节律紊乱的对夜尿症的全新理解。采用多学科的方法，结合尿动力学测量与转基因分析、分子生物学和电生理学，将探讨BK通道在膀胱功能日常调节中的作用。这项拟议工作的第一个具体目标是通过收缩研究、电生理学记录BK电流和分析蛋白质表达来确定膀胱平滑肌在昼夜之间的功能差异。第二个具体目标将通过在Kcnma1-/-和其他转基因小鼠系中进行膀胱测速来确定膀胱功能昼夜变化的机制，解决膀胱和中枢大脑通路的相互作用。这些研究有可能确定一种全新的膀胱功能控制机制和新水平。所提出的研究对于阐明治疗人类患者夜尿症的关键机制具有重要意义。 与公共卫生相关：夜尿症，即夜间排尿过多，是一种常见且经常持续的疾病，影响某些年龄段50%的人，并显著降低生活质量。这项拟议的研究的目的是为控制正常的昼夜(昼夜)排尿模式以及夜尿症可能出错的鲜为人知的过程开发一种机械解释。