Diabetic Uropathy Pathobiology Site

描述(由申请人提供)： 糖尿病尿病是指一系列令人衰弱的泌尿系并发症，如膀胱功能障碍、尿失禁、尿路感染和性功能障碍，这些并发症是糖尿病(DM)最常见、最昂贵、但尚未得到充分研究的并发症之一。糖尿病是一种不治之症，在美国至少有2000万人受到影响，随着肥胖率的迅速上升，糖尿病的患病率正在上升。糖尿病尿路病变的治疗选择不足，而且在过去50年中没有改善。为响应RFA-DK-05-011，我们建议与糖尿病并发症动物模型联合会的组织结构合作，以发挥‘糖尿病尿路病变病理生物学站点’的作用，参与开发两种新的糖尿病尿路病变小鼠模型，并研究这些动物糖尿病膀胱功能障碍的病理生理学机制。 根据观察到的糖尿病对小动物膀胱功能的时间效应，我们推测，成年小鼠平滑肌中特异性的锰超氧化物歧化酶(MnSOD)的耗竭将加剧STZ诱导的糖尿病期间平滑肌中自由基的积累，并加速糖尿病膀胱功能障碍失代偿期的开始。我们进一步假设，通过限制STZ诱导的自由基积聚到血管系统的加剧，限制MnSOD对动脉平滑肌的耗竭对STZ诱导的糖尿病膀胱功能障碍的影响较小。在MnSODlox/lox、SMCreERT2小鼠和MnSODlox/lox、ASM-CreERT2小鼠中，选择性地耗尽总和动脉平滑肌中的MnSOD将通过注射4-羟基三苯氧胺来激活在平滑肌中表达的Cre重组酶来完成。这些动物将进一步接受4-羟基三苯氧胺治疗，其中一半将注射STZ以诱发糖尿病。动物的膀胱功能将通过四个特定的目标来研究：1)通过排尿习惯和有意识的膀胱测速，体内膀胱功能的时间变化；2)糖尿病引起的膀胱肥大的形态变化的时间过程；3)逼尿肌收缩功能的时间变化；4)支配膀胱的传入和传出自主神经通路的时间变化。 首席调查员和研究小组自2003年以来一直是现有AMDCC的一部分，在国家卫生研究院以及AMDCC的指导委员会和外部咨询委员会的主持下发挥了良好的作用。

DESCRIPTION (provided by applicant): Diabetic Uropathy is a term for a range of debilitating urologic complications such as bladder dysfunction, urinary incontinence, urinary tract infection and sexual dysfunction, that are among the most common and costly, yet understudied complications of diabetes mellitus (DM), an incurable disease that affects at least 20 million people in the U.S. and is rising in prevalence with the rapidly rising prevalence of obesity. Therapeutic options for diabetic uropathy are inadequate and have not improved over the last 50 years. In response to RFA-DK-05-011, we propose to work with the Animal Models of Diabetic Complications Consortium's organizational structure to function as the 'Diabetic Uropathy Pathobiology Site" to participate in development of two novel mice models of diabetic uropathy and to investigate the mechanisms of the pathophysiology of diabetic bladder dysfunction in these animals. Based on the observed temporal effects of diabetes on the bladder function in small animals, we hypothesize that depletion of manganese superoxide dismutase (MnSOD) specifically in smooth muscle of adult mice will exacerbate accumulation of free radicals in smooth muscle during STZ-induced diabetes and accelerate the onset of the decompensated phase of diabetic bladder dysfunction. We hypothesize further that limiting depletion of MnSOD to arterial smooth muscle will have a lesser effect on STZ-induced diabetic bladder dysfunction by limiting exacerbation of STZ-induced free radical accumulation to the vasculature. Depletion of MnSOD selectively in total and arterial smooth muscle in the MnSODlox/lox, SMCreERT2 mice and MnSODlox/lox, ASM-CreERT2 mice, respectively, will be accomplished by administration of 4-hydroxytamoxifen to activate Cre recombinase expressed in the smooth muscle. The animals will be further treated with 4-hydroxytamoxifen treatment, and half of them will be injected with STZ to induce diabetes. The bladder function in the animals will be studied via four specific aims to examine: 1) the temporal alterations in the in-vivo bladder function by micturition habits and conscious cystometry; 2) the temporal course of morphological changes in diabetes-induced bladder hypertrophy; 3) temporal alterations in the contractile function of the detrusor muscle; 4) the temporal alterations in afferent and efferent autonomic pathways innervating the bladder. The Principal Investigator and the research team have a productive track record in being a part of the existing AMDCC since 2003 and have functioned well under the auspices of the NIH, and the Steering and External Advisory Committees of the AMDCC.