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

系统遗传学模型定义的与年龄相关的排尿功能障碍的机制

• 批准号: 8549234
• 负责人: Mark L. Zeidel
• 金额: $ 32.02万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-29 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8549234
• 关键词: Affect; Aging; Alleles; American; Anesthesia procedures; Animals; Appearance; Behavior; Biological Assay; Bladder; Bladder Dysfunction; Cardiovascular system; Collaborations; Complex; Data; Defect; Development; Disease; Effectiveness; Elderly; Environment; Etiology; Exhibits; Exposure to; Failure; Financial cost; Functional disorder; Funding; Genes; Genetic; Genetic Models; Genetic Variation; Human; Hypertrophy; Inbred Mouse; Inbred Strain; Inbreeding; Increased frequency of micturition; Individual; Kidney; Knock-out; Location; Longevity; Lower urinary tract; Maps; Metabolic; Modeling; Molecular; Mouse Strains; Mus; Outcome; Overactive Bladder; Paper; Pattern; Phenotype; Physiological; Population; Proteins; Quantitative Trait Loci; Randomized; Recombinants; Reflex action; Resources; Specialized Center; Spottings; Stress Urinary Incontinence; Symptoms; Syndrome; System; TNFRSF5 gene; The Jackson Laboratory; Urethral sphincter; Urine; Urodynamics; Urothelium; age related; aged; assay development; awake; base; design; genetic linkage; genetic resource; human disease; improved; interest; lower urinary tract symptoms; micturition urgency; mouse model; novel; public health relevance; relating to nervous system; trait; urinary; urine overflow incontinence

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.

描述（由申请人提供）：较低的尿路症状（LUTS）是令人衰弱的疾病，包括过度活跃的膀胱，压力和溢流尿失禁，尿频和紧急性，随着人类衰老而变得越来越普遍。这些症状困扰着数百万的人类和财务成本的美国人。由于LUTS是异质的，并且病因学很少了解，因此治疗是经验性和有效性有限的。为了改善对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测定，用于在小鼠（无效点测定法）中开发较低的尿路（LUT）功能障碍。正常的年轻小鼠在笼子里的过滤纸上单个位置上无效，我们称这种行为是“正常的尿位定位”，而膀胱功能障碍的小鼠和许多老化小鼠在笼子底部的底部无效，“尿液定位异常”。使用该测定法在麻醉和清醒下的细胞体图（CMG）等复杂功能测定过程中跟随小鼠，以及对尿道括约肌功能的研究，我们将利用小鼠中艺术系统遗传学的状态并使用P20机制（开发PRELIMINIC PLESINAL INGETION和PLENINE机构），以识别以下机制，以下是1：1。在人类中。 2。开发小鼠人类LUTS的强大模型。 3。确定小鼠衰老的生理变化的发展与衰老小鼠中LUT的发展并联的程度。