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Murine slow onset outlet obstruction as a model of human voiding dysfunction

小鼠缓慢发作的出口梗阻作为人类排尿功能障碍的模型

基本信息

批准号：
7920714
负责人：
RONALD W WOOD
金额：
$ 9.82万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-28 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7920714
关键词：
Acute Adrenergic alpha-Antagonists Adult Adverse effects Age Aging Animal Disease Models Animals Area Attention Autopsy Basic Science Benign Benign Prostatic Hypertrophy Biological Models Bladder Bladder Diseases Breeding Characteristics Chronic Clinic Clinical Clinical Management Detection Development Dilatation - action Disease Disease model Dose Dutasteride Esthesia Evaluation Event Fibrosis Figs - dietary Financial compensation Frequencies Functional disorder Future Genes Gland Goals Histologic Histopathology Human Hydronephrosis Hyperplasia Hypertrophy Image Immunohistochemistry In Situ In Situ Hybridization Increased frequency of micturition Individual Inflammation Investigation Kidney Knock-out Knowledge Laboratory Animals Ligation Ligature Link Lobe Longevity Lower urinary tract Malignant Neoplasms Measures Mechanics Methods Modeling Molecular Monitor Mouse Strains Mus Neoplasms Nocturia Obstruction Onset of illness Oral Organ Oxidoreductase Palpable Patients Pattern Pelvis Peritoneal Pharmaceutical Preparations Phase Phenotype Physiological Pilot Projects Pre-Clinical Model Principal Investigator Process Prolactin Prostate Prostate Adenocarcinoma Prostatic Prostatic hypertrophy Relative (related person)Research Research Design Research Personnel Residual volume Risk Seminal Vesicles Severities Signal Transduction Solid Staging Stanolone Surface System Technology Testing Testosterone Text Therapeutic Thick Time Tissue Banks Tissues Tolterodine Transgenic Mice Transgenic Organisms Treatment Efficacy Ureter Urethra Urethritis Urinary Retention Urodynamics Validation Weight Wood material aged animal model development awake constriction drug development human disease imaging modality improved in vivo inhibitor/antagonist innovation interest lower urinary tract symptoms men mouse model novel outcome forecast overexpression pressure prevent probasin programs prostate enlargement remediation research study response skills soft tissue tool tumor urinary urinary bladder neck urine overflow incontinence wasting

项目摘要

DESCRIPTION (provided by applicant): Aging men manifest Benign Prostatic Hyperplasia (BPH) that can result in lower urinary tract symptoms (LUTS), decreased flow, prolonged voiding, detrusor instability (Dl), nocturia, retention, and hydronephrosis. Preclinical models mimic this by suddenly tightening a ligature around the urethra, resulting in onset of Dl in a few weeks; instant onset of urethral constriction is likely to differ importantly from partial outlet obstruction that takes five or more decades to develop in humans and months in mice. After developing methods to measure uroflow and void duration in the awake mouse, we turned our attention to several transgenic mouse strains (TRAMP, TRAMP-FVB, MPAKT and PbPRL) known to develop urinary obstruction associated with probasin-driven expression systems. Changes in voiding function typical of outlet obstruction have occurred in two strains to date. Automated image capture confirmed prolonged pulsatile voiding, not overflow incontinence. Histologic study confirmed neoplasia, suburethral gland enlargement, and other changes consistent with obstruction. The MPAKT mouse is documented to obstruct at >400 days in the absence of invasive cancer. The PbPRL mouse also obstructs associated with prolactin-induced benign hyperplasia. These transgenic mice show promise as nonsurgical models of slow-onset bladder outlet obstruction. We will monitor the development of voiding dysfunction, and measure prostate size noninvasively using soft tissue conebeam computed tomographic methods (conebeam CT). Contrast studies offer detection of the onset of ureterohydronephrosis, bladder vesiculation, and increased bladder wall thickness in vivo. Histopathology will be used to confirm imaging findings, and to describe potential bladder hypertrophy and fibrosis. Pharmacologic challenges with medications used for clinical management of BPH will be administered across their lifespan to reveal functionally silent compensatory changes in voiding function, and to demonstrate therapeutic enhancement of impaired voiding function. We expect to describe three stages of BPH in the mouse, i.e. asymptomatic, dysfunctional, and hydronephrotic, and to observe compensatory and decompensation processes. Development of mouse models of the lower urinary tract symptoms seen in benign prostatic hypertrophy and other bladder diseases are expected to generate increased understanding of the underlying disease process, and eventually to help predict how the disease will progress in individual patients. Many medications are developed by studying effects in normal animals, because true models of the disease do not exist. Valid animal models of disease should respond similarly to patients treated with prescription medications. Such models help identify new types of medications as well as their likelihood of side effects.

描述（由申请人提供）：老年男性表现为良性前列腺增生（BPH），可导致下尿路症状（LUTS），流量减少，排尿时间延长，逼尿肌不稳定（Dl），夜尿症，尿潴留和肾积水。临床前模型通过突然收紧尿道周围的结扎来模拟这种情况，导致Dl在几周内发作；即刻发生的尿道收缩可能与部分出口梗阻有重要区别，后者在人类中需要50年或更长时间才能形成，在小鼠中需要数月。在开发了测量清醒小鼠尿流和空腔持续时间的方法后，我们将注意力转向了几种已知与probasin驱动表达系统相关的尿路梗阻的转基因小鼠菌株（TRAMP, trump - fvb， MPAKT和PbPRL）。排尿功能的改变是排尿出口梗阻的典型表现，迄今为止已有两种菌株出现。自动图像捕捉确认为长时间的搏动性排尿，而非溢溢性尿失禁。组织学检查证实肿瘤、喉下腺肿大及其他与梗阻一致的改变。在没有侵袭性癌症的情况下，MPAKT小鼠在bb0 - 400天阻滞。PbPRL小鼠也有与催乳素诱导的良性增生相关的阻塞。这些转基因小鼠有望成为慢性膀胱出口梗阻的非手术模型。我们将监测排尿功能障碍的发展，并使用软组织锥束计算机断层扫描方法（锥束CT）无创性地测量前列腺大小。对比研究可以在体内检测输尿管积水、膀胱水肿和膀胱壁厚度增加的发病情况。组织病理学将用于证实影像学发现，并描述潜在的膀胱肥大和纤维化。BPH临床治疗药物的药理学挑战将贯穿患者的整个生命周期，以揭示功能沉默的排尿功能代偿性变化，并证明对排尿功能受损的治疗增强。我们期望描述小鼠BPH的三个阶段，即无症状、功能失调和肾积水，并观察代偿和失代偿过程。在良性前列腺肥大和其他膀胱疾病中发现的下尿路症状的小鼠模型的发展有望增加对潜在疾病过程的理解，并最终帮助预测疾病在个体患者中的进展。许多药物都是通过研究正常动物的效果来开发的，因为这种疾病的真正模型并不存在。有效的疾病动物模型应该对接受处方药治疗的患者有类似的反应。这些模型有助于确定新型药物及其副作用的可能性。