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

描述（由申请人提供）：下尿路症状（LUTS）是一系列衰弱性疾病，包括膀胱过度活动、压力和溢流性尿失禁、尿频和尿急，随着人类年龄的增长，这些症状越来越普遍。这些症状折磨着数以百万计的美国人，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，效果有限。为了改善LUTS的治疗，我们必须提高对其原因的理解。我们开发了一种无创的检测小鼠下尿路（LUT）功能障碍的方法，即空洞斑点法。正常的年轻老鼠在笼子里的滤纸上的一个地方排空，我们称之为“正常的尿定位”，而膀胱功能障碍的老鼠和许多年老的老鼠在笼子的底部排空，“异常的尿定位”。利用这种方法跟踪小鼠的整个生命周期，以及在麻醉和清醒状态下进行复杂的功能分析，如膀胱造影（CMGs）和尿道括约肌功能的研究，我们将利用最先进的小鼠系统遗传学，利用P20机制（开发初步数据）和P50机制来完成以下目标：在小鼠中鉴定可能引起人类LUTS的新基因。2. 在小鼠中建立稳健的人类LUTS模型。3. 确定小鼠衰老生理变化的发展在多大程度上与衰老小鼠LUT的发展并行。

DESCRIPTION (provided by applicant): 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 mice 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.