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

项目总结 多发性硬化症(MS)是一种影响中枢神经系统(CNS)的自发性炎症性疾病 美国大约有40万人，全球有超过210万人。下尿路 70%-90%的MS患者存在尿路症状(LUT)，包括尿频、尿急、 大小便失禁、夜尿、膀胱排空不全、尿流减弱和尿潴留。我们最近 描述了一种新的由冠状病毒引起的神经原性膀胱功能障碍的小鼠模型。病毒 在中枢神经系统中触发急性炎症(冠状病毒诱导的脑脊髓炎，CIE模型)，然后 大脑和脊髓出现进行性脱髓鞘。CIE小鼠出现明显的神经功能缺陷 与排尿功能障碍相关，这与在MS患者中观察到的神经源性LUTS相似。这个 CIE小鼠神经源性LUTS的机制包括神经元中心的形态变化 控制排尿，激活脊髓神经胶质细胞，增加促炎细胞因子的表达 感染期，并增强了膀胱收缩的嘌呤能反应。我们最近的研究进行了一项 对CIE小鼠的长期随访发现了3种不同的神经退行性症状表型 发展：1-神经退行性变的慢性进展并持续出现症状(C-PRO 组)，2-出现几个缓解-复发发作(C-RELAP组)，以及3-从初始状态恢复 疾病急性期后症状(REC组)。各型患者排尿方式的尿动力学评价 亚组显示，C-RELAP组小鼠表现出最严重的神经源性膀胱过度活动 与较低的膀胱容量、缩短的两次排尿间隔和较低的排尿压力有关。 因此，CIE模型为比较三大类神经源性LUT提供了独特的机会。 人类多发性硬化症的类型(缓解型、慢性型和复发-缓解型)。这个应用程序建立在我们最初的发现之上， 并将揭示神经源性LUT的详细系统和细胞机制，以改善 多发性硬化患者下尿路感染的评估、诊断和护理。特定目标1将决定脊髓神经胶质细胞的作用 中枢(脊髓)和外周(感觉和运动)神经元信号调节中的激活(胶质细胞增多症) 自主神经节)参与排尿控制的中枢。我们将评估两者之间的机械联系 早期、晚期脊髓神经胶质细胞活化与膀胱神经细胞功能变化 和多发性硬化症进展的慢性阶段。特定目标2将测试靶向免疫治疗的改善能力 在MS小鼠模型中的神经源性LUTS拟议的实验将利用神经解剖学、生化、 电生理学、药理学、药物遗传学、免疫治疗和行为实验 全面评估神经原性膀胱发生的机制 功能障碍。这项研究的结果将对该病的诊断、治疗和预防产生重大影响 MS等神经退行性疾病患者的神经源性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.