Lower urinary tract symptoms (LUTS) are a spectrum of debilitating disorders, including overactive bladder, stress and overflow incontinence, urinary frequency and urgency, which become increasingly prevalent with aging in humans. These symptoms afflict millions of Americans with enormous human and financial costs. Because LUTS is heterogeneous and etiology is poorly understood, treatment is empiric and of limited effectiveness. To improve therapy for LUTS, we must improve our understanding of its causes. We have developed a noninvasive assay for the development of lower urinary tract (LUT) dysfunction in mice, the void spot assay. Normal young mice void in a single spot on filter papers in their cages, a behavior which we term, "normal urinary localization," while mice with bladder dysfunction and many aging mice void all over the bottom of the cage, "abnormal urinary localization." Using this assay to follow mice over their lifespan as well as sophisticated functional assays such as cystometrograms (CMGs) under anesthesia and awake and studies of urethral sphincter function, we will harness state of the art systems genetics in mice and use the P20 mechanism (to develop preliminary data) and the P50 mechanism to complete the following aims: 1. To identify novel genes in mice which are likely to cause LUTS in humans. 2. To develop robust models of human LUTS in mice. 3. To determine the extent to which the development of physiological changes of aging in mice progress in parallel with the development of LUT in aging mice.
Lower urinary tract syndrome (LUTS) causes enormous debility in the elderly population, yet because we know little about why it occurs our treatments often fail to help. The proposed studies will identify new genes that cause LUTS in mice and will create robust mouse models of this difficult human disease.
|Bjorling, Dale E; Wang, Zunyi; Vezina, Chad M et al. (2015) Evaluation of voiding assays in mice: impact of genetic strains and sex. Am J Physiol Renal Physiol 308:F1369-78|
|Hill, Warren G (2015) Control of urinary drainage and voiding. Clin J Am Soc Nephrol 10:480-92|
|Ackert-Bicknell, Cheryl L; Anderson, Laura C; Sheehan, Susan et al. (2015) Aging Research Using Mouse Models. Curr Protoc Mouse Biol 5:95-133|
|Yu, Weiqun; Ackert-Bicknell, Cheryl; Larigakis, John D et al. (2014) Spontaneous voiding by mice reveals strain-specific lower urinary tract function to be a quantitative genetic trait. Am J Physiol Renal Physiol 306:F1296-307|