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: 8462969
• 负责人: Firouz Daneshgari
• 金额: $ 32.95万
• 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/8462969
• 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.

描述（由申请人提供）：我们的长期目标是揭示糖尿病性膀胱功能障碍（DBD）的潜在机制，DBD是糖尿病（DM）最常见和致残的并发症之一，并开发治疗DBD的治疗方法。DBD是一系列以膀胱排空不良和尿失禁为主要特征的异常，对其病理生理学和机制的了解还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动物t1d相关膀胱功能障碍（T1D-BD）的研究中，我们已经确定了DBD的多种表现的时间依赖性，包括与渗透诱导的多尿相关的早期代偿变化（储存问题）和后期代偿变化，表现为排尿问题。基于这项工作和其他小组的结果，我们假设：i)在糖尿病的早期，渗透诱导的多尿引起膀胱的快速肥大和重塑，涉及神经源性和肌源性成分，导致代偿性储存问题。ii)糖尿病晚期，长期高血糖对膀胱的影响，不仅限于多尿，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) DM晚期对LUT组织的损伤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，大部分是由长期的高血糖引起的。根据我们使用LUT功能障碍的小型啮齿动物模型的既定记录，并使用我们实验室最近创建的三种创新方法[输尿管至子宫颈的尿转移（UD），膀胱传入感觉功能的评估，以及具有条件的，平滑肌选择性缺失锰超氧化物歧化酶（MnSOD）基因的转基因小鼠]，我们将在两个特定目标中验证我们的假设：目的1：通过比较链脲霉素（STZ）诱导的糖尿病、利尿或假药治疗对有或没有UD的大鼠的功能和神经化学变化，来区分高血糖和多尿在T1D-BD时间进展中的作用。为了确定氧化应激在T1D-BD发病中的机制作用，通过比较STZ诱导的DM小鼠在时间进展过程中膀胱功能、形态和分子的变化，包括平滑肌选择性缺失MnSOD、MnSOD整体过表达或药物诱导的氧化应激或神经病变的衰减。我们的研究团队和合作者在DBD的转化研究方面拥有最高水平的专业知识。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的全面见解。