PROJECT SUMMARYThe overall goal of this project is to examine the role of oxidative stress in the pathogenesis ofurinary incontinence (UI), including urge UI (overactive bladder /detrusor overactivity) and stressUI, in obesity/pre-type 2 diabetes mellitus (O/pre-T2DM). Obese and/or type 2 diabeticindividuals, especially women, are at a substantial risk of developing UI. Furthermore, obesityand T2DM are strongly associated with systemic oxidative stress and inflammation. Wepreviously discovered that, in rodent models of type 1 diabetes, bladder dysfunction follows atemporal 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, butthe time course and mechanisms of UI phenotypes associated with those conditions remainunknown. Now we propose to study mechanisms of UI in O/pre-T2DM by taking advantage ofour two newly developed animal models, conditional smooth muscle-specific Sod2 knockoutmice and mice with simulated birth trauma, as well as a new technique to measure bladdersensation 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 byantioxidant treatment, and 2) stress UI in O/pre-T2DM requires an additional insult such asvaginal delivery/birth trauma. We will test our hypotheses via two Specific Aims: In SA #1, wewill assess the pathogenesis of detrusor overactivity in male and female C57BL/6 mice with highfat 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 themanganese superoxide dismutase gene (Sod2-/- mice), relative to lean controls. Assays willinclude conscious cystometry, contractile responses of bladder detrusor strips, neuroselectivemeasurement of bladder sensation, and a novel MRI acquisition and image analysis techniqueto assess body lipid burden. In SA #2, we will assess recovery from vaginal distension-inducedstress 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 pointpressure, urethral morphology and innervation, and body lipid burden. Successful completion ofthese studies will provide critical leads for prevention and therapy of UI in O/pre-T2DM.
|Effective start/end date||7/19/16 → 5/31/21|
- National Institutes of Health: $347,148.00
Type 2 Diabetes Mellitus
Overactive Urinary Bladder
Inbred C57BL Mouse
Wounds and Injuries
Type 1 Diabetes Mellitus