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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK089337-02
Application #
8118835
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Hoshizaki, Deborah K
Project Start
2010-08-01
Project End
2014-07-31
Budget Start
2011-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2011
Total Cost
$183,080
Indirect Cost
Name
University of Maryland Baltimore
Department
Physiology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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