权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
7318919
负责人：
RONALD W WOOD
金额：
$ 27.12万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7318919
关键词：
Acute Adrenergic alpha-Antagonists Adult Adverse effects Age Aging Animal Disease Models Animal Model Animals Area Attention Autopsy Basic Science Benign Benign Prostatic Hypertrophy Biological Models Bladder Bladder Diseases Breeding Characteristics Chronic Class Clinic Clinical Clinical Management Constriction procedure 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 Invasive 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 Numbers Obstruction Onset of illness Oral Organ Oxidoreductase Palpable Pathological Dilatation Patients Pattern Pelvis Peritoneal Pharmaceutical Preparations Phase Phenotype Physiological Pilot Projects Pre-Clinical Model Principal Investigator Process Prolactin Prostate Prostate Adenocarcinoma Prostatic Prostatic hypertrophy Protein Overexpression 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 Urination Urodynamics Validation Week Weight Wood material aged awake day drug development human disease improved in vivo inhibitor/antagonist innovation interest lower urinary tract symptoms men mouse model novel outcome forecast prescription document prescription procedure pressure prevent probasin programs prostate enlargement remediation research study response size 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症(BPH)，可导致下尿路症状(LUTS)、尿流减少、排尿时间延长、逼尿肌不稳定(DL)、夜尿、尿潴留和肾积水。临床前模型通过突然收紧尿路周围的结扎来模拟这种情况，导致几周内出现DL；立即出现的尿路狭窄可能与部分出口梗阻有很大不同，后者在人类需要50年或更长时间才能发展，在老鼠身上需要几个月。在开发了测量清醒小鼠尿流和排尿持续时间的方法后，我们将注意力转向几个已知与前盆驱动表达系统相关的尿路梗阻的转基因小鼠品系(TRAMP、TRAMP-FVB、MPAKT和PbPRL)。到目前为止，有两种菌株出现了典型的出口梗阻的排尿功能变化。自动图像采集证实了长时间的搏动性排尿，而不是溢出性尿失禁。组织学检查证实肿瘤形成、尿道腺增大和其他与梗阻相一致的改变。MPAKT小鼠被证明在没有浸润性癌症的情况下可以在AT&gt；400天内受阻。PbPRL小鼠还可阻断与催乳素诱导的良性增生相关的作用。这些转基因小鼠有望成为慢性起病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CT方法(锥束CT)非侵入性测量前列腺大小。对比研究提供了体内发生输尿管肾积水、膀胱囊化和膀胱壁增厚的检测。组织病理学将用于确认影像表现，并描述潜在的膀胱肥大和纤维化。用于临床治疗BPH的药物的药理学挑战将在他们的整个生命周期内进行，以揭示排尿功能的静默代偿性变化，并证明对受损的排尿功能的治疗增强。我们期望描述小鼠BPH的三个阶段，即无症状、功能障碍和肾积水，并观察代偿和失代偿过程。建立良性前列腺肥大和其他膀胱疾病中出现的下尿路症状的小鼠模型，有望增加对潜在疾病过程的了解，并最终帮助预测疾病在个别患者中的进展情况。许多药物是通过研究对正常动物的影响而开发出来的，因为这种疾病的真实模型并不存在。有效的疾病动物模型的反应应该与使用处方药治疗的患者相似。这类模型有助于识别新型药物及其副作用的可能性。