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

描述(申请人提供)：下尿路症状(LUTS)是一系列衰弱的疾病，包括膀胱过度活跃、压力和溢流性尿失禁、尿频和尿急，随着年龄的增长，这些症状在人类中变得越来越普遍。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，疗效有限。要提高对LUTS的治疗水平，必须提高对其病因的认识。我们开发了一种非侵入性的小鼠下尿路(LUT)功能障碍的检测方法，即空白点检测。正常的幼鼠在它们笼子里的滤纸上只有一个斑点是空的，这种行为我们称之为“正常的尿液定位”，而有膀胱功能障碍的小鼠和许多衰老的小鼠在笼子的底部到处都是空的，称为“异常的尿液定位”。利用这项测试跟踪小鼠的寿命，以及复杂的功能分析，如麻醉和清醒状态下的膀胱测定仪(CMGs)和对尿路括约肌功能的研究，我们将利用小鼠最先进的系统遗传学，并使用P20机制(开发初步数据)和P50机制来完成以下目标：1.在小鼠中鉴定可能导致人类LUTS的新基因。2.建立健壮的人LUTS小鼠模型。3.确定小鼠衰老生理变化的发展与老年小鼠LUT发展的平行程度。

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.