Mechanism and Prevention of Female Stress Urinary Incontinence

描述（由申请人提供）：压力性尿失禁影响着美国数百万女性，并对生活质量产生了实质性的负面影响。目前对于压力性尿失禁（SUI），除了用缝合线或合成吊带进行手术抬高尿道外，没有有效的预防或医疗选择。我们目前的研究已经证实，在模拟分娩创伤的动物模型中，雌激素治疗增加了失禁的机会。尿失禁增加的机制似乎包括尿道α肾上腺素能受体表达的紊乱，细胞信使RhoA、ROCK-I、ROCK-II和磷酸化肌球蛋白轻链（pMLC）表达的变化，以及尿道胶原I和弹性纤维含量的减少。为了制定SUI的预防措施，我们注意到在我们的动物模型中，早期给药生长激素显著降低了尿失禁率。保留尿道内的弹性纤维和胶原纤维是减少尿失禁最重要的因素。由于神经肌肉对尿失禁的贡献已经被广泛研究，在本次更新申请中，我们建议研究细胞外胶原蛋白和弹性纤维对尿道正常功能的贡献。对于这些研究，我们将使用活细胞/组织成像和分子生物学技术。此外，我们将测试一种安全、廉价的策略来预防尿失禁，并开发一个长期、慢性尿失禁模型来测试治疗方案。我们的目标是将我们实验室获得的知识转化为患有SUI的女性的临床应用。

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.