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

项目摘要 该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UI（膀胱过度活动症/逼尿肌过度活动症）和压力 UI，肥胖/2型糖尿病前期（O/pre-T2 DM）。肥胖和/或2型糖尿病 个人，尤其是女性，有很大的风险发展UI。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，膀胱功能障碍发生在 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T2 DM中UI的不同自然史，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，我们建议利用以下方法研究O/pre-T2 DM中UI的机制： 我们新开发的两种动物模型，条件性平滑肌特异性Sod 2敲除， 小鼠和模拟分娩创伤的小鼠，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/前- 2型糖尿病是由肥胖相关的氧化应激增加介导的，可以通过以下方式缓解： 抗氧化剂治疗，和2）O/pre-T2 DM中的应激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测试我们的假设：在SA #1中，我们 将评估具有高血压的雄性和雌性C57 BL/6小鼠中逼尿肌过度活动的发病机制。 脂肪饮食（HFD）诱导的肥胖，有或没有用抗氧化剂MitoQ治疗，在HFD- 喂食条件性平滑肌特异性缺失的雄性和雌性C57 BL/6小鼠， 锰超氧化物歧化酶基因（Sod 2-/-小鼠），相对于瘦对照。测定将 包括有意识膀胱测压、膀胱逼尿肌条收缩反应、神经选择性 测量膀胱感觉，以及一种新的MRI采集和图像分析技术 以评估身体脂质负担。在SA #2中，我们将评估从阴道扩张引起的 在有或没有MitoQ治疗的HFD喂养的雌性肥胖雌性小鼠中，以及在HFD- 喂食雌性肥胖Sod 2-/-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。成功完成 这些研究将为O/pre-T2 DM患者UI的预防和治疗提供重要线索。

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.