Mechanism of Type I and II Caused Diabetic Bladder Dysfunction

描述(申请人提供)：我们的长期目标是揭示糖尿病(DM)最常见和最令人丧失能力的并发症之一--糖尿病膀胱功能障碍(DBD)的潜在机制，并开发DBD的根治疗法。DBD是一种以膀胱排空障碍和尿失禁为主要特征的一系列异常，对DBD的病理生理学和机制的了解一直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，涉及与渗透性多尿(储存问题)相关的早期代偿性变化，以及后来表现为排尿问题的失代偿性变化。基于这项工作和其他研究小组的结果，我们假设：1)在糖尿病早期，渗透性多尿引起膀胱的快速肥大和重塑，包括神经源性和肌源性成分，导致代偿性储存问题。Ii)在糖尿病晚期，除多尿外，长期高血糖对膀胱的影响会对神经和肌肉功能造成不可逆转的损害，导致膀胱失代偿性排尿问题。3)晚期糖尿病对LUT组织的损害主要是由于氧化应激产物的积聚，部分是由肥大引起的，大部分是由于长期的高血糖所致。在我们既有的LUT功能障碍啮齿动物模型的基础上，利用我们实验室最近发明的三种创新方法[从输尿管到宫颈的尿流改道(UD)、膀胱传入感觉功能的评估，以及有条件的、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下验证我们的假设：SA#1-通过比较链脲佐菌素(STZ)诱导的糖尿病、利尿或假治疗后糖尿病、利尿或假治疗后大鼠的功能和神经化学变化，来区分高血糖和多尿在T1D-BD的时间进展中的作用。SA#2-通过比较STZ诱导的糖尿病小鼠的膀胱功能、形态和分子变化，确定氧化应激在T1D-BD发病机制中的作用，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减轻。我们的研究团队和合作者在DBD的翻译研究方面拥有最高水平的专业知识之一。通过这项合作，这项提案产生的数据将为DBD的发病机制和有效预防或治疗DBD的潜在治疗目标提供重要的全面见解。 公共卫生相关性：糖尿病(DM)是一组虚弱且代价高昂的疾病，具有多种严重并发症，在美国折磨着2500万人，估计到2030年全球将有3.66亿人受到影响。糖尿病膀胱功能障碍(DBD)以膀胱排空障碍和尿失禁为特征，是糖尿病最常见和最严重的并发症之一。然而，对DBD的病理生理学和发病机制知之甚少，使得数以百万计的患者没有有效的治疗选择。我们的研究团队是DBD研究的领先者之一。我们观察了DBD多种表现的时间依赖性，并在DBD动物模型中解释了DBD的自然历史。在此基础上，我们建议通过确定多尿、高血糖和氧化应激在代偿性和失代偿性DBD形成中的作用来研究DBD早期和晚期膀胱功能障碍的机制。在我们关于DBD的工作的继续中，这项提议产生的数据将对DBD的发病机制和有效预防或治疗DBD的潜在治疗靶点产生一些最全面的见解。

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. 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.