Mechanisms of age-related voiding dysfunction defined by systems genetics models

下尿路症状(LUT)是一系列衰弱的疾病，包括膀胱过度活动， 压力性和溢流性尿失禁，尿频和尿急，随着 人类的衰老。这些症状折磨着数百万美国人，付出了巨大的人力和经济代价。 由于LUTS是异质性的，病因尚不清楚，治疗是经验性的和有限的。 有效性。要提高对LUTS的治疗水平，必须提高对其病因的认识。我们有 开发了一种用于小鼠下尿路(LUT)功能障碍的非侵入性检测方法 斑点分析。正常的幼鼠在它们笼子里的滤纸上只有一个点是空的，这是我们 术语“正常的尿液定位”，而膀胱功能障碍的小鼠和许多衰老的小鼠全身都是空的 笼底“尿液定位异常”。使用这种测试来跟踪它们的生命周期 以及复杂的功能分析，如麻醉和清醒状态下的膀胱测定仪(CMG)和 关于尿道括约肌功能的研究，我们将利用小鼠最先进的系统遗传学，并使用 P20机制(制定初步数据)和P50机制完成以下目标：1. 在小鼠身上识别可能导致人类下尿路感染的新基因。2.开发稳健的模型 小鼠体内的人LUTS。3.确定在多大程度上发展生理变化 小鼠的衰老过程与老年小鼠的LUT的发展是平行的。

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 nhice 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.