Mechanisms of Neurogenic Bladder Dysfunction in EAE Mice

描述(申请人提供)：神经源性尿失禁(NUI)是神经源性膀胱功能障碍(NBD)最麻烦的表现。NBD统称为由多发性硬化症(MS)等神经系统问题引起的膀胱功能障碍。多发性硬化症是最常见的致残性神经疾病，影响20至45岁的女性。MS是一种进行性退行性自身免疫性疾病，由于整个神经系统的脱髓鞘病变而损害神经元功能，影响膀胱及其出口的功能。多发性硬化症在女性中的发生率是男性的两倍，超过80%的多发性硬化症女性患者存在NUI。在患病时间超过10年的患者中，NUI的患病率上升到96%以上。虽然MS相关性NBD和NUI的基本病理生理学机制仍不清楚，但有人认为NBD的发生是由于脱髓鞘干扰了连接中枢神经系统控制和膀胱的脊髓和周围神经通路以及下尿路功能的神经通路，从而扰乱了膀胱功能的储存期和排尿期。因此，尿失禁可能是由于膀胱储存失败(急迫性尿失禁)或排空失败(溢出性尿失禁)所致。此外，多发性硬化症具有不可预测的缓解和复发模式的波动性质，使多发性硬化症患者的膀胱功能恶化，导致与多发性硬化症相关的发病率和死亡率的沉重负担。我们最近创建了一种模拟人类多发性硬化症临床过程的NBD小鼠模型，包括储存功能障碍、排尿问题和逼尿肌括约肌协同失调(DSD)。实验性自身免疫性脑脊髓炎(EAE)小鼠为我们提供了一个独特的机会来研究与NBD和NUI相关的关键悬而未决的研究问题。我们假设临床评分为0-4的雌性SWXJ小鼠表现出与NBD类型相对应的储尿或排尿功能障碍。进一步，我们假设，患有DSD的膀胱出口梗阻模式的小鼠由于膀胱无反射而出现溢流性尿失禁，而没有DSD的小鼠由于膀胱反射亢进而出现膀胱过度活动(OAB)和急迫性尿失禁。这些假说将通过三个具体目标进行检验。目的1通过同时进行膀胱测压和肌电分析，评价EAE中NBD储存期和排尿期的时间特征。目的2将研究EAE小鼠中枢神经系统组织病理学和神经功能缺陷与NBD储存和排尿阶段的关系。最后，Aim 3将在体外检测整个神经源性膀胱的收缩反应。这种动物模型与同时评估膀胱和出口功能的创新方法相结合，将使我们能够以一种全新的方式研究NUI的机制，为数百万患有NUI的女性发现预防和治疗干预措施打开大门。 公共卫生相关性：神经源性尿失禁(NUI)是神经源性膀胱功能障碍(NBD)最麻烦的表现。NBD统称为由多发性硬化症(MS)等神经系统问题引起的膀胱功能障碍。膀胱有两个主要功能：储存尿液和排空。在NUI中，这两种功能中的任何一种都可能受损。利用MS小鼠模型，我们将研究NUI的具体机制，从而合理地设计预防和治疗干预措施。

DESCRIPTION (provided by applicant): Neurogenic Urinary Incontinence (NUI) is the most bothersome manifestation of Neurogenic Bladder Dysfunction (NBD). NBD refers collectively to bladder dysfunctions that are caused by neurological problems such as multiple sclerosis (MS). MS is the most common disabling neurological disorder affecting women between 20 and 45 years old. MS is a progressive degenerative autoimmune disease that impairs neuronal functions due to demyelinating lesions throughout the nervous system, affecting the function of the bladder and its outlet. MS is twice as frequent in women as in men, and more than 80% of women with MS present with NUI. The prevalence of NUI rises to more than 96% in those with the disease for longer than 10 years. While the underlying pathophysiology of MS-associated NBD and NUI remains poorly understood, it is suggested that NBD occurs as a result of demyelination interrupting the neural pathways connecting the central nervous system control to the spinal and peripheral neuronal pathways of the bladder and lower urinary tract function, thus disrupting both the storage and voiding phase of bladder function. Thus, NUI can present as a result of failure of bladder storage (urge incontinence) or emptying (overflow incontinence). Further, the fluctuating nature of MS with unpredictable patterns of remissions and relapses exposes women with MS to deteriorating bladder function that contributes to the heavy burden of morbidity and mortality associated with MS. We have recently created a mouse model of NBD that mimics the clinical course of MS in humans, including storage dysfunction, voiding problems and detrusor sphincter dyssynergia (DSD). The mouse with Experimental Autoimmune Encephalomyelitis (EAE) has afforded us with the unique opportunity to investigate the key unanswered research questions related to NBD and NUI. We hypothesize that female SWXJ mice with EAE in clinical scores 0-4 demonstrate a corresponding storage or voiding bladder dysfunction predictive of the type of NBD. Further, we hypothesize that mice with bladder outlet obstructive pattern from DSD have overflow incontinence due to areflexia bladder, and mice without DSD have overactive bladder (OAB) and urge incontinence due to hyperreflexia bladder. The hypotheses will be tested with three specific aims. In aim 1 the temporal characteristics of storage and voiding phases of NBD in EAE will be assessed by simultaneous cystometrogram and electromyogram. Aim 2 will correlate CNS histopathology and neurologic deficit with defined storage and voiding phases of NBD in EAE mice. Finally, aim 3 will examine contractile responses of the whole neurogenic bladder in vitro. This animal model combined with innovative methods of simultaneous assessment of bladder and outlet function, will allow us to investigate the mechanisms of NUI in a whole new way, opening the gates for discovery of preventive and therapeutic interventions for millions of women suffering from NUI. PUBLIC HEALTH RELEVANCE: Neurogenic Urinary Incontinence (NUI) is the most bothersome manifestation of Neurogenic Bladder Dysfunction (NBD). NBD refers collectively to bladder dysfunctions that are caused by neurological problems such as multiple sclerosis (MS). The bladder has two primary functions urine storage and emptying. In NUI either of these functions might be impaired. Using a mouse model of MS, we will investigate the specific mechanism of NUI leading to rational design of preventive and therapeutic interventions.