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

• 批准号: 9754115
• 负责人: Firouz Daneshgari
• 金额: $ 35.66万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 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/9754115
• 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; Exposure to; Female; Fiber; Genes; Goals; High Fat Diet; Image Analysis; Impairment; 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; Thinness; Time; Tissues; Type 2 diabetic; United States; Urethra; Urge Incontinence; Urinary Incontinence; Urodynamics; Urology; Vagina; Vaginal delivery procedure; Woman; Work; antioxidant therapy; base; course development; diabetic; experimental study; feeding; innovation; insight; lower urinary tract symptoms; male; micturition urgency; modifiable risk; nerve supply; novel; pressure; prevent; repaired; response; translational approach; urologic

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.

项目总结 本项目的总体目标是研究氧化应激在糖尿病发病机制中的作用。 尿失禁(UI)，包括急迫性尿失禁(膀胱过度活动/逼尿肌过度活动)和压力 肥胖/2型糖尿病前期(O/T2 DM前期)。肥胖和/或2型糖尿病 个人，尤其是女性，有很大的患尿崩症的风险。此外，肥胖 和T2 DM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 从补偿阶段到失代偿阶段的时间进程。最近， 我们和其他人已经开始揭示肥胖和T2 DM中不同的尿失禁自然病史，但 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，我们建议通过研究O/Pre-T2 DM患者的尿失禁机制 我们新开发的两种动物模型，条件性平滑肌特异性Sod2基因敲除 模拟出生创伤的小鼠和小鼠，以及测量膀胱的新技术 在老鼠身上的感觉。根据我们目前的观察，我们假设：1)O/Pre中的用户界面- 2型糖尿病是由肥胖相关的氧化应激增加所介导的，并可通过以下方法缓解 抗氧化剂治疗，以及2)O/Pre-T2 DM的应激UI需要额外的侮辱，如 阴道分娩/分娩创伤。我们将通过两个具体目标来测试我们的假设：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)诱导的肥胖，无论是否使用抗氧化剂MitoQ治疗，以及在HFD- 给雄性和雌性C57BL/6小鼠饲喂条件性平滑肌特异性缺失 锰超氧化物歧化酶基因(Sod2-/-小鼠)，相对于瘦肉对照。化验结果会 包括有意识膀胱测压、膀胱逼尿肌条收缩反应、神经选择性 膀胱感觉的测量，以及一种新的MRI采集和图像分析技术 以评估身体的脂肪负荷。在SA#2中，我们将评估由阴道扩张引起的恢复情况 高脂饲料喂养的雌性肥胖雌性小鼠在接受或不接受MitoQ治疗的情况下，以及在高脂饲料喂养的 喂食雌性肥胖Sod2-/-小鼠，相对于瘦体重对照，使用泄漏点测量 压力，尿路形态和神经，以及体脂负荷。成功完成 这些研究将为O/Pre-T2 DM患者尿失禁的预防和治疗提供重要线索。