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Phenotrypes and Mechanisms of Urinary Incontinence in Obesity/pre-Type 2 Diabetes

肥胖/2 型糖尿病前期的尿失禁表型和机制

基本信息

批准号：
9160437
负责人：
Firouz Daneshgari
金额：
$ 34.71万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-19 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9160437
关键词：
Affect Aging Animal Model Antioxidants Biological Assay Birth trauma Bladder Bladder Dysfunction Body fat C57BL/6 Mouse Characteristics Chronic stress Clinical Clinical Research Communities Complications of Diabetes Mellitus Conscious Development Diabetes Mellitus Diagnosis Diagnostic Disease Esthesia Female Fiber Genes Goals High Fat Diet Image Analysis Individual Inflammation Insulin-Dependent Diabetes Mellitus Knockout Mice Lead Lipids Literature Lower urinary tract Magnetic Resonance Imaging Measurement Measures Mediating Mitochondria Morphology Mus Natural History Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Operative Surgical Procedures Overactive Bladder Oxidative Stress Pathogenesis Pharmacotherapy Phase Phenotype Play Positioning Attribute Prediabetes syndrome Prevalence Prevention therapy Preventive Quality of life Recovery Reporting Risk Risk Factors Rodent Model Role SOD2 gene Smooth Muscle Stress Urinary Incontinence Symptoms Techniques Testing Therapeutic Time Tissues United States Urethra Urge Incontinence Urinary Incontinence Urodynamics Urology Vagina Vaginal delivery procedure Woman Work antioxidant therapy base course development diabetic feeding innovation insight lower urinary tract symptoms male modifiable risk nerve supply novel pressure prevent repaired research study response translational approach urologic

项目摘要

PROJECT SUMMARY The overall goal of this project is to examine the role of oxidative stress in the pathogenesis of urinary incontinence (UI), including urge UI (overactive bladder /detrusor overactivity) and stress UI, in obesity/pre-type 2 diabetes mellitus (O/pre-T2DM). Obese and/or type 2 diabetic individuals, especially women, are at a substantial risk of developing UI. Furthermore, obesity and T2DM are strongly associated with systemic oxidative stress and inflammation. We previously discovered that, in rodent models of type 1 diabetes, bladder dysfunction follows a temporal course of progression from a compensated to a decompensated phase. More recently, we and others have begun to uncover a different natural history of UI in obesity and T2DM, but the time course and mechanisms of UI phenotypes associated with those conditions remain unknown. Now we propose to study mechanisms of UI in O/pre-T2DM by taking advantage of our two newly developed animal models, conditional smooth muscle-specific Sod2 knockout mice and mice with simulated birth trauma, as well as a new technique to measure bladder sensation in mice. Based on our current observations, we hypothesize that: 1) UI in O/pre- T2DM is mediated by obesity-associated increased oxidative stress and can be alleviated by antioxidant treatment, and 2) stress UI in O/pre-T2DM requires an additional insult such as vaginal delivery/birth trauma. We will test our hypotheses via two Specific Aims: In SA #1, we will assess the pathogenesis of detrusor overactivity in male and female C57BL/6 mice with high fat diet (HFD)-induced obesity, with or without treatment with the antioxidant MitoQ, and in HFD- fed male and female C57BL/6 mice with conditional smooth muscle specific deletion of the manganese superoxide dismutase gene (Sod2-/- mice), relative to lean controls. Assays will include conscious cystometry, contractile responses of bladder detrusor strips, neuroselective measurement of bladder sensation, and a novel MRI acquisition and image analysis technique to assess body lipid burden. In SA #2, we will assess recovery from vaginal distension-induced stress UI in HFD-fed, female obese female mice with or without MitoQ treatment, and in HFD- fed, female obese Sod2-/- mice, relative to lean controls, using measurements of leak point pressure, urethral morphology and innervation, and body lipid burden. Successful completion of these studies will provide critical leads for prevention and therapy of UI in O/pre-T2DM.

项目概要该项目的总体目标是检查氧化应激在发病机制中的作用尿失禁 (UI)，包括尿失禁（膀胱过度活动症/逼尿肌过度活动）和压力 UI，肥胖/2 型糖尿病前期 (O/T2DM 前期)。肥胖和/或 2 型糖尿病个人，尤其是女性，面临着患 UI 的巨大风险。此外，肥胖和 T2DM 与全身氧化应激和炎症密切相关。我们先前发现，在 1 型糖尿病的啮齿动物模型中，膀胱功能障碍遵循从代偿期进展到失代偿期的时间过程。最近，我们和其他人已经开始发现肥胖和 T2DM 中 UI 的不同自然史，但是与这些条件相关的 UI 表型的时间进程和机制仍然存在未知。现在我们建议利用 O/pre-T2DM 中的 UI 机制进行研究我们新开发的两种动物模型，条件性平滑肌特异性 Sod2 敲除小鼠和模拟产伤小鼠，以及测量膀胱的新技术小鼠的感觉。根据我们目前的观察，我们假设：1）O/pre-中的UI T2DM 由肥胖相关的氧化应激增加介导，可以通过以下方法缓解：抗氧化治疗，以及 2) O/T2DM 前期的应激 UI 需要额外的损伤，例如阴道分娩/产伤。我们将通过两个具体目标来检验我们的假设：在 SA #1 中，我们将评估雄性和雌性 C57BL/6 小鼠逼尿肌过度活动的发病机制脂肪饮食 (HFD) 引起的肥胖，无论是否接受抗氧化剂 MitoQ 治疗，以及 HFD- 喂养雄性和雌性 C57BL/6 小鼠，条件性平滑肌特异性删除锰超氧化物歧化酶基因（Sod2-/- 小鼠），相对于瘦对照。化验将包括有意识的膀胱测压、膀胱逼尿肌条的收缩反应、神经选择性膀胱感觉测量以及新型 MRI 采集和图像分析技术评估身体脂质负担。在 SA #2 中，我们将评估阴道扩张引起的恢复情况 HFD 喂养的雌性肥胖雌性小鼠（接受或不接受 MitoQ 治疗）以及 HFD- 喂养的雌性肥胖 Sod2-/- 小鼠，相对于瘦对照，使用泄漏点测量压力、尿道形态和神经支配以及身体脂质负担。顺利完成这些研究将为 O/T2DM 前期 UI 的预防和治疗提供重要线索。