Murine slow onset outlet obstruction as a model of human voiding dysfunction

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DESCRIPTION (provided by applicant): Aging men manifest Benign Prostatic Hyperplasia (BPH) that can result in lower urinary tract symptoms (LUTS), decreased flow, prolonged voiding, detrusor instability (Dl), nocturia, retention, and hydronephrosis. Preclinical models mimic this by suddenly tightening a ligature around the urethra, resulting in onset of Dl in a few weeks; instant onset of urethral constriction is likely to differ importantly from partial outlet obstruction that takes five or more decades to develop in humans and months in mice. After developing methods to measure uroflow and void duration in the awake mouse, we turned our attention to several transgenic mouse strains (TRAMP, TRAMP-FVB, MPAKT and PbPRL) known to develop urinary obstruction associated with probasin-driven expression systems. Changes in voiding function typical of outlet obstruction have occurred in two strains to date. Automated image capture confirmed prolonged pulsatile voiding, not overflow incontinence. Histologic study confirmed neoplasia, suburethral gland enlargement, and other changes consistent with obstruction. The MPAKT mouse is documented to obstruct at >400 days in the absence of invasive cancer. The PbPRL mouse also obstructs associated with prolactin-induced benign hyperplasia. These transgenic mice show promise as nonsurgical models of slow-onset bladder outlet obstruction. We will monitor the development of voiding dysfunction, and measure prostate size noninvasively using soft tissue conebeam computed tomographic methods (conebeam CT). Contrast studies offer detection of the onset of ureterohydronephrosis, bladder vesiculation, and increased bladder wall thickness in vivo. Histopathology will be used to confirm imaging findings, and to describe potential bladder hypertrophy and fibrosis. Pharmacologic challenges with medications used for clinical management of BPH will be administered across their lifespan to reveal functionally silent compensatory changes in voiding function, and to demonstrate therapeutic enhancement of impaired voiding function. We expect to describe three stages of BPH in the mouse, i.e. asymptomatic, dysfunctional, and hydronephrotic, and to observe compensatory and decompensation processes. Development of mouse models of the lower urinary tract symptoms seen in benign prostatic hypertrophy and other bladder diseases are expected to generate increased understanding of the underlying disease process, and eventually to help predict how the disease will progress in individual patients. Many medications are developed by studying effects in normal animals, because true models of the disease do not exist. Valid animal models of disease should respond similarly to patients treated with prescription medications. Such models help identify new types of medications as well as their likelihood of side effects.