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）是一系列使人衰弱的疾病，包括膀胱过度活动症、压力性和溢流性尿失禁、尿频和尿急，这些症状随着人类的衰老而变得越来越普遍。这些症状折磨着数百万美国人，付出了巨大的人力和财力代价。由于下尿路症状是异质性的，病因学知之甚少，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。我们已经开发了一种非侵入性测定小鼠下尿路（LUT）功能障碍的发展，空斑试验。正常的年轻小鼠在笼子里的滤纸上的一个点上排尿，我们称之为“正常的尿定位”，而膀胱功能障碍的小鼠和许多老年小鼠在笼子底部排尿，“异常的尿定位”。“使用这种测定方法来跟踪小鼠的寿命以及复杂的功能测定，如麻醉和清醒下的膀胱测压图（CMG）以及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（开发初步数据）和P50机制来完成以下目标：1.确定小鼠中可能导致人类LUTS的新基因。2.在小鼠中建立人LUTS的稳健模型。3.确定小鼠衰老生理变化的发展与衰老小鼠LUT的发展平行的程度。

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.