Mechanisms of neurogenic bladder dysfunction in a viral murine model of multiple sclerosis

项目摘要 多发性硬化（MS）是中枢神经系统（CNS）的自身炎症性疾病， 美国约有40万人，全球超过210万人。下泌尿 在70-90%的MS患者中存在尿路症状（LUTS），包括尿频，尿急， 尿失禁、排尿困难、膀胱排空不全、尿流微弱和尿潴留。我们最近 表征了由冠状病毒诱导的神经源性膀胱功能障碍的新小鼠模型。病毒 引发CNS急性炎症（冠状病毒诱导的脑脊髓炎，CIE模型）， 大脑和脊髓的进行性脱髓鞘。CIE小鼠出现显著的神经功能缺损 与排尿功能障碍相关，与MS患者中观察到的神经性LUTS相当。的 CIE小鼠中神经源性LUTS的潜在机制包括神经元中心的形态学变化 控制排尿，激活脊髓胶质细胞，增加急性期促炎细胞因子的表达 感染期，并增强膀胱收缩的嘌呤能反应。我们最近的研究显示， 对CIE小鼠进行长期随访，发现3种不同的神经退行性症状表型 发展：1-神经变性的慢性进展，伴随症状的持续存在（C-PRO 组），2 -存在几次缓解-复发发作（C-REESTING组），3 -从初始 疾病急性期后的症状（REC组）。尿动力学评价排尿模式， 亚组显示，C-RESINS组小鼠表现出最严重的神经源性膀胱过度活动 与膀胱容量降低、排尿间隔缩短和排尿压力降低相关。 因此，CIE模型提供了一个独特的机会，比较神经源性LUTS在三个主要的 人类MS类型（缓解型、慢性和复发缓解型）。这个应用程序建立在我们最初的发现之上， 并将揭示详细的系统和细胞机制的神经源性LUTS，以改善 MS患者LUTS的评估、诊断和护理。具体目标1将确定脊髓胶质细胞的作用 在中枢（脊髓）和外周（感觉和运动）神经元信号传导的调节中的激活（神经胶质增生 自主神经节）中枢参与排尿的控制。我们将评估 脊髓胶质细胞活化和膀胱神经支配神经元的功能变化 和MS进展的慢性阶段。特异性目标2将测试靶向免疫治疗改善 神经源性LUTS在MS的鼠模型中。所提出的实验将利用神经解剖学，生物化学， 电生理学、药理学、药物遗传学、免疫学和行为学实验， 为神经源性膀胱的发生机制提供全面的评估 功能障碍本研究结果将对该病的诊断、治疗和预防产生重大影响 神经退行性疾病如MS患者的神经源性LUTS。

PROJECT SUMMARY Multiple sclerosis (MS) is an auto-inflammatory disease of the central nervous system (CNS) that affects approximately 400,000 people in the United States and more than 2.1 million people worldwide. Lower urinary tract symptoms (LUTS) are present in 70–90% of MS patients, and include urinary frequency, urgency, incontinence, nocturia, incomplete bladder emptying, weak stream, and retention of urine. We recently characterized a new mouse model of neurogenic bladder dysfunction induced by a coronavirus. The virus triggers acute inflammation in the CNS (coronavirus-induced encephalomyelitis, CIE model) followed by progressive demyelination in the brain and spinal cord. CIE mice develop a significant neurologic deficit associated with voiding dysfunction that is comparable with neurogenic LUTS observed in MS patients. The mechanisms underlying neurogenic LUTS in CIE mice include morphological changes in the neuronal centers controlling micturition, activation of spinal glia, increased expression of pro-inflammatory cytokines during acute phase of infection, and enhanced purinergic responses of bladder contractions. Our recent study performed a long-term follow up of CIE mice and revealed 3 differential phenotypes of neurodegenerative symptom development: 1-chronic progression of neurodegeneration with continuous presence of symptoms (C-PRO group), 2 – presence of several remission-relapsing episodes (C-RELAP group), and 3 - recovery from initial symptoms after acute phase of the disease (REC group). Urodynamic evaluation of voiding patterns in each subgroup revealed that mice in C-RELAP group showed the most severe neurogenic bladder overactivity associated with lower bladder capacity, reduced inter-micturition interval, and decreased pressure at micturition. Therefore, the CIE model provides a unique opportunity for the comparison of neurogenic LUTS in three major types of human MS (remissive, chronic and relapsing-remitting). This application builds upon our initial findings, and will uncover the detailed systemic and cellular mechanisms of neurogenic LUTS in order to improve the assessment, diagnosis, and care of LUTS in MS patients. Specific Aim 1 will determine the role of spinal glia activation (gliosis) in modulation of neuronal signaling in the central (spinal) and peripheral (sensory and motor autonomic ganglia) centers involved in the control of micturition. We will evaluate the mechanistic link between glial activation in the spinal cord and functional changes in bladder innervating neurons during early, advanced and chronic stages of MS progression. Specific Aim 2 will test the ability of targeted immunotherapy to improve neurogenic LUTS in a murine model of MS. The proposed experiments will utilize neuroanatomical, biochemical, electrophysiological, pharmacological, pharmacogenetic, immunotherapeutic, and behavioral experiments to provide a comprehensive assessment of the mechanisms underlying the development of neurogenic bladder dysfunction. The results of this study will have a major impact on the diagnosis, treatment and prevention of neurogenic LUTS in patients with neurodegenerative disorders such as MS.