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

下尿路症状（LUTS）是一系列使人衰弱的疾病，包括膀胱过度活动症， 压力性和溢出性尿失禁、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财力代价。 由于下尿路症状的异质性和病因学知之甚少，治疗是经验性的和有限的 有效性为了改善LUTS的治疗，我们必须提高对其原因的理解。我们有 开发了一种非侵入性测定小鼠下尿路（LUT）功能障碍的方法， 斑点试验正常的年轻老鼠在笼子里的滤纸上的一个单一的点上排泄， 术语“正常尿定位”，而膀胱功能障碍的小鼠和许多衰老小鼠全身排尿 笼子的底部，“异常尿定位。“使用这种测定来跟踪nhice的寿命， 以及复杂的功能测定，如麻醉和清醒状态下的膀胱测量图（CMG）， 尿道括约肌功能的研究中，我们将利用最先进的系统遗传学在小鼠和使用 P20机制（制定初步数据）和P50机制完成以下目标：1.到 在小鼠中鉴定可能导致人类LUTS的新基因。2.建立健全的模型， 小鼠中的人LUTS。3.为了确定在何种程度上发展的生理变化， 小鼠的衰老与衰老小鼠中LUT的发展平行。

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.