Mechanism and Prevention of Female Stress Urinary Incontinence

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DESCRIPTION (provided by applicant): Stress urinary incontinence affects millions of women in the United States and has substantial negative effects on quality of life. There is currently no effective preventive or medical option for stress urinary incontinence (SUI) other than surgical elevation of the urethra with sutures or a synthetic sling. Our current grant has confirmed that treatment with estrogen increase the chances of incontinence in our animal model of simulated birth trauma. The mechanisms underlying this increase in incontinence appeared to include perturbations of urethral alpha adrenergic receptor expression, changes in expression of the cellular messengers RhoA, ROCK-I, ROCK-II, and phosphorylated myosin light chain (pMLC), and reduction in urethral collagen I and elastic fiber content. In an attempt to develop preventive measures for SUI, we noted that early administration of growth hormone significantly reduced the incontinence rate in our animal model. Preservation of elastic and collagen fibers in the urethra was the factor most strongly associated with reduction of incontinence. Since the neuromuscular contributions to continence have already been extensively studied, in this renewal application we propose to study the contribution of the extracellular collagen and elastic fibers to the normal function of the urethra. For these studies we will use living cell/tissue imaging and molecular biology technique. In addition, we will test a safe and inexpensive strategy to prevent incontinence as well as develop a long-term, chronic incontinence model to test treatment options. Our goal is to translate the knowledge obtained in our laboratory to clinical applications for women suffering from SUI. PUBLIC HEALTH RELEVANCE: Urinary leakage with coughing, sneezing or exercise (aka stress urinary incontinence, SUI) is a common medical problem in middle-aged and older women. In our current study, we determined that disruption of elastic and collagen fibers in the urethra is strongly associated with urine leakage in an animal model of SUI. This grant proposal will study means to stop birth-trauma mediated disruption of collagen and elastic fibers before it takes place and/or enhance repair of these fibers.