Mechanism of Type I and II Caused Diabetic Bladder Dysfunction

I型和II型引起糖尿病膀胱功能障碍的机制

• 批准号: 8300520
• 负责人: Firouz Daneshgari
• 金额: $ 34.15万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300520
• 关键词: Acetylcysteine; Affect; Animal Model; Antioxidants; Bladder; Bladder Dysfunction; Bypass; C57BL/6 Mouse; Cells; Centers for Disease Control and Prevention (U.S.); Cervix Uteri; Clinical; Collaborations; Collection; Complications of Diabetes Mellitus; Data; Dependence; Development; Diabetes Mellitus; Diagnosis; Disease; Diuresis; Drug vehicle; Elements; Enzymes; Esthesia; Exhibits; Functional disorder; Generations; Genes; Goals; High Prevalence; Hyperglycemia; Hypertrophy; Individual; Insulin-Dependent Diabetes Mellitus; Knowledge; Laboratories; Long-Term Effects; Lower urinary tract; Manganese Superoxide Dismutase; Mitochondria; Modification; Molecular; Mus; Muscle; Natural History; Nerve; Neuropathy; Operative Surgical Procedures; Oxidative Stress; Pancreas; Pathogenesis; Patients; Pharmaceutical Preparations; Placebos; Play; Polyuria; Population; Rattus; Research; Research Design; Residual state; Rodent; Rodent Model; Role; Sensory; Sensory Thresholds; Smooth Muscle; Sprague-Dawley Rats; Staging; Streptozocin; Sucrose; Symptoms; Testing; Time; Tissues; Transgenic Mice; Ureter; Urge Incontinence; Urinary Diversion; Urinary Incontinence; Urine; Urothelial Cell; Urothelium; Wild Type Mouse; Work; aged; attenuation; base; diabetic; disorder prevention; effective therapy; innovation; insight; neurochemistry; novel; overexpression; prevent; research study; response; therapeutic target; translational study

DESCRIPTION (provided by applicant): Our long term goals are to uncover the mechanisms underlying diabetic bladder dysfunction (DBD), one of the most common and incapacitating complications of the diabetes mellitus (DM), and develop curative therapies for DBD. Knowledge of the pathophysiology and mechanisms of DBD, a range of abnormalities characterized mainly by poor emptying of the bladder and urinary incontinence, has been inadequate for development of effective treatments. In our previous and ongoing studies of T1D-related bladder dysfunction (T1D-BD) in rodents, we have identified the time dependence of the multiple manifestations of DBD, involving early compensatory changes associated with osmotically-induced polyuria (storage problems) and later decompensatory changes manifest as voiding problems. Based on this work and results of other groups, we hypothesize that: i) In the early stage of DM, osmotically induced polyuria causes rapid hypertrophy and remodeling of the bladder involving both neurogenic and myogenic components, leading to compensatory storage problems. ii) In the later stage of DM, effects of long-term hyperglycemia on the bladder, beyond polyuria, cause irreversible damages to the functions of nerves and muscles, leading to decompensatory voiding problems of the bladder. iii) The damages to LUT tissues in late stage DM are caused mainly by accumulation of oxidative stress products induced partly by hypertrophy and mostly by prolonged hyperglycemia. Drawing on our established track record using small rodent models of LUT dysfunction, and using three innovative approaches created recently in our laboratory [urinary diversion (UD) from the ureters to the cervix, assessment of afferent sensory function of the bladder, and transgenic mice with conditional, smooth muscle-selective deletion of the manganese superoxide dismutase (MnSOD) gene], we will test our hypotheses in two Specific Aims: SA#1- To distinguish the roles of hyperglycemia and polyuria in the temporal progression of T1D-BD, by comparing the functional and neurochemical changes that follow streptozotocin (STZ)-induced DM, diuresis, or sham treatment in rats with or without UD. SA#2- To determine the mechanistic role of oxidative stress in the pathogenesis of T1D-BD, by comparing the functional, morphological and molecular changes in the bladder during the temporal progression of STZ induced DM in mice with smooth muscle-selective deletion of MnSOD, global overexpression of MnSOD, or drug-induced attenuation of oxidative stress or neuropathy. Our research team and collaborators have one of the highest levels of expertise in translational studies of DBD. Through this collaboration, the data generated from this proposal will provide Significant comprehensive insights into the pathogenesis of DBD and on potential therapeutic targets to prevent or treat DBD effectively. PUBLIC HEALTH RELEVANCE: Diabetes mellitus (DM) is a group of debilitating and costly diseases with multiple serious complications that afflict 25 million people in the U.S. and is estimated to affect 366 million worldwide by 2030. Diabetic bladder dysfunction (DBD), characterized by poor emptying of the bladder and urinary incontinence, is among the most common and incapacitating complications of DM. However, poor knowledge of the pathophysiology and mechanisms of DBD leaves millions of patients with ineffective management options. Our research team is among the leading groups in the study of DBD. We have observed the time-dependence of multiple manifestations of DBD, and explained the natural history of DBD in animal models of DBD. Based on that work, we now propose to study the mechanisms of the bladder dysfunction at early and late stage of DBD by identification of roles of polyuria, hyperglycemia, and oxidative stress on creation of compensated and decompensated DBD. In continuation of our work on DBD, the data generated from this proposal would yield some of the most comprehensive insights into the pathogenesis of DBD and on potential therapeutic targets to prevent or treat DBD effectively.

描述（由申请人提供）：我们的长期目标是揭示糖尿病膀胱功能障碍（DBD）的潜在机制，糖尿病膀胱功能障碍（DBD）是糖尿病（DM）最常见和致残的并发症之一，并开发针对 DBD 的治疗方法。 DBD 是一系列主要以膀胱排空不良和尿失禁为特征的异常现象，但对 DBD 的病理生理学和机制的了解尚不足以开发有效的治疗方法。在我们之前和正在进行的啮齿类 T1D 相关膀胱功能障碍 (T1D-BD) 研究中，我们已经确定了 DBD 多种表现的时间依赖性，包括与渗透性多尿（储存问题）相关的早期代偿性变化和表现为排尿问题的后期失代偿性变化。基于这项工作和其他小组的结果，我们假设：i）在 DM 的早期阶段，渗透性诱导的多尿导致膀胱快速肥大和重塑，涉及神经源性和肌源性成分，导致代偿性储存问题。 ii) 在糖尿病后期，长期高血糖对膀胱的影响，除了多尿之外，还会对神经和肌肉功能造成不可逆的损害，导致膀胱失代偿性排尿问题。 iii) 晚期DM对LUT组织的损害主要是由氧化应激产物的积累引起的，部分是由肥大引起的，大部分是由长期高血糖引起的。借鉴我们使用 LUT 功能障碍的小型啮齿动物模型建立的记录，并使用我们实验室最近创建的三种创新方法 [从输尿管到子宫颈的尿流改道 (UD)、膀胱传入感觉功能的评估以及有条件、平滑肌选择性删除锰超氧化物歧化酶 (MnSOD) 基因的转基因小鼠]，我们将测试我们的假设 两个具体目标： SA#1 - 通过比较链脲佐菌素 (STZ) 诱导的糖尿病、利尿或假治疗后患有或不患有 UD 的大鼠的功能和神经化学变化，区分高血糖和多尿在 T1D-BD 时间进展中的作用。 SA#2-通过比较平滑肌选择性缺失 MnSOD、整体过度表达 MnSOD 或药物诱导的氧化应激或神经病变减轻的小鼠在 STZ 诱导的 DM 时间进展过程中膀胱的功能、形态和分子变化，确定氧化应激在 T1D-BD 发病机制中的机制作用。我们的研究团队和合作者在 DBD 转化研究方面拥有最高水平的专业知识之一。通过此次合作，该提案产生的数据将为 DBD 的发病机制以及有效预防或治疗 DBD 的潜在治疗靶点提供重要、全面的见解。 公共健康相关性：糖尿病 (DM) 是一组使人衰弱且代价高昂的疾病，具有多种严重并发症，在美国影响着 2500 万人，预计到 2030 年将影响到全球 3.66 亿人。糖尿病膀胱功能障碍 (DBD) 的特点是膀胱排空不良和尿失禁，是 DM 最常见和致残的并发症之一。然而，由于对 DBD 的病理生理学和机制了解不足，导致数百万患者无法获得有效的治疗选择。我们的研究团队是DBD研究的领先团队之一。我们观察了 DBD 多种表现的时间依赖性，并解释了 DBD 动物模型中 DBD 的自然史。基于这项工作，我们现在建议通过确定多尿、高血糖和氧化应激在代偿性和失代偿性 DBD 产生中的作用来研究 DBD 早期和晚期膀胱功能障碍的机制。为了继续我们在 DBD 方面的工作，该提案产生的数据将为 DBD 的发病机制以及有效预防或治疗 DBD 的潜在治疗靶点提供一些最全面的见解。