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

基本信息

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
项目类别：
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

项目摘要

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膀胱功能障碍（DBD）的机制，这是糖尿病（DM）最常见和最无能为力的并发症之一，并为DBD开发治疗疗法。了解DBD的病理生理学和机制的知识，这是一系列异常，主要是膀胱排空和尿失禁的排空不足，因此无法用于开发有效治疗。在啮齿动物中T1D相关的膀胱功能障碍（T1D-BD）的先前和正在进行的研究中，我们已经确定了DBD多重表现的时间依赖性，涉及与渗透诱导的多尿液（存储问题）相关的早期补偿性变化，而后来的代偿性变化表现为散布问题。基于其他群体的这项工作和结果，我们假设：i）在DM的早期阶段，渗透诱导的多尿症会引起快速肥大和膀胱的重塑，涉及神经源性和肌源性成分，导致补偿性存储问题。 ii）在DM的后期，长期高血糖对膀胱的影响，除了多尿中，造成神经和肌肉功能的不可逆转的损害，从而导致膀胱的不足性缺失问题。 iii）在晚期DM中对LUT组织的损害主要是由氧化应激产物的积累部分由肥大诱导的氧化应激产物，主要是由于长期高血糖症。 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在两个具体目的中：SA＃1-通过比较伴随着链蛋白酶（STZ）诱导的DM，DIURESIS，或在与UD的大鼠中进行假治疗的功能性和神经化学变化，以区分高血糖和多尿中T1D-BD的时间进展中的作用。 SA＃2-通过比较MNSOD的平滑肌肌肉选择性，MNSSOD，药物诱导的氧化应变或氧化应激的全球过度表达，氧化应激在T1D-BD的发病机理中的机理作用，通过比较膀胱诱导的DM的功能，形态和分子变化。我们的研究团队和合作者在DBD翻译研究中拥有最高水平的专业知识之一。通过这种合作，该提案产生的数据将为DBD的发病机理和潜在的治疗靶标提供重要的全面见解，以有效预防或治疗DBD。