Mechanism of Type I and II Caused Diabetic Bladder Dysfunction

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）（糖尿病（DM）最常见和致残性并发症之一）的潜在机制，并开发DBD的治愈性疗法。DBD是一系列以膀胱排空不良和尿失禁为主要特征的异常，其病理生理学和机制的知识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T1 D相关膀胱功能障碍（T1 D-BD）的研究中，我们已经确定了DBD的多种表现的时间依赖性，包括与禁食诱导的多尿（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，糖尿病诱导的多尿引起涉及神经源性和肌源性成分的膀胱的快速肥大和重塑，导致代偿性储存问题。ii）在DM的后期，长期高血糖对膀胱的影响，除了多尿之外，对神经和肌肉的功能造成不可逆的损害，导致膀胱的失代偿性排尿问题。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引起的，氧化应激产物部分由肥大诱导，大部分由长期高血糖诱导。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[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，以及锰超氧化物歧化酶（MnSOD）基因有条件的平滑肌选择性缺失的转基因小鼠]，我们将在两个特定目标中测试我们的假设：SA#1-通过比较伴或不伴UD的大鼠中链脲佐菌素（STZ）诱导的DM、利尿或假治疗后的功能和神经化学变化，区分高血糖和多尿在T1 D-BD时间进展中的作用。SA#2-通过比较在具有平滑肌选择性MnSOD缺失、MnSOD整体过表达或药物诱导的氧化应激或神经病变减弱的小鼠中STZ诱导的DM的时间进展期间膀胱中的功能、形态学和分子变化，确定氧化应激在T1 D-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。通过这次合作，该提案产生的数据将为DBD的发病机制和有效预防或治疗DBD的潜在治疗靶点提供重要的全面见解。

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.